UroGen Pharma Ltd. (URGN) Earnings Call Transcript & Summary

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. And this is our agenda for the morning. Our CEO, Liz Barrett, will come up to the podium in just a moment. We're going to have presentations by some scholars in the field as well as a very important data discussion and release. And then finally, a panel discussion and a Q&A. So we look forward to having a very interesting and robust conversation this morning about some very exciting data. And with that, let me welcome Liz Barrett, CEO of UroGen to the podium.

Thanks, Mark. Thank you for being here, as Mark said. So I just wanted to give my thanks as well. Also I 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. And the rest of our Board members are online. So happy to have you all here. I've been trying to teach Mark to get out of his doctor tone, but he can't do that. So I'm going to do it for him. They often -- I get often asked often about highlight of your career, what's the thing you're most proud of. So let me be very clear, it's today. I mean it really is. I have 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. And I know you hear that a lot, and you think, "Well, is it really true?" Trust me, it's really true. And so, I'm really proud at the time I started in oncology. The survival rate for cancer patients across all different types of cancers was pretty dismal. And we've made so many advances over the years to be where we are today. And so when I got the call from a recruiter saying, Arie Belldegrun, whom I've never met at the time, wants to talk to you about UroGen, and I was sort of like, I don't know. I've never heard of UroGen. I've been around a long time, probably not a good time. And they said, "Just talk to him for a few minutes." And I don't know how many of you guys know Arie, but saying no to Arie is almost impossible. And so what he said to me was, just talk to the team, just talk to the team. So I did. So I said, okay, okay. I'll go into New York, and I'll talk to the team. And it's 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 blocking. So I was actually really surprised. And then the other thing 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. And I was like, wow, I mean, that also in my 25 years being in oncology doesn't happen very often. And so 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, but now what we're going to be able to do, hopefully, assuming we get approval in a bladder cancer is just amazing. So I hope that you find today is compelling and is exciting as we find it, and we really are looking forward to sharing the data with you today. So with that, I want to just talk a little bit about -- for some reason, it's not moving. Sorry, the slides aren't moving. There we go. And with that, I do believe that Urogen of all companies is uniquely positioned in this space, and I'm going to talk to you about why. 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 they're doing -- urologists are doing a great job with them with what they have, but for us to be able to actually change the paradigm for these patients. And we sort of took a step back and said, why. So we believe that patients deserve better. And 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 they call it RTGel. And 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. But 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. The body turns to gel, delivers medicine. And what that does is it 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. And we've seen that both in our data on JELMYTO and now our data on UGN-102. And so because of that, it disintegrates naturally in your inflow and 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 U.S. alone living with the bladder cancer. It's also one of the most recurrent cancers. And so these patients, they come in, they get their treatment and their 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 multi-focal disease. They tend to recur more often. 68% of those will have 2 or more recurrences and 23% will have 5 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 that urothelial is, whether the tumor is in the upper track of the bladder, genetically and the mutationally are very similar. And so and the products are very similar. They're not the same. We often get that question. It's not the same, but they both use the technology, our RTGel technology, in combination with mitomycin. And so for that, you see a lot -- there are many of us who expected we will see positive results in bladder cancer. Because, we feel like the disease is very similar. But 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 on a fluoroscopy, so that you do it in the right way. The market is very small. So you really have 6,000 to 7,000 patients for JELMYTO. So it's hard to find them. So any one urologist might only have 1 or 2 patients. Not the case with UGN-102, a much larger patient population, you're going to hear from the physician panel very shortly. And every physician, every urologist sees these patients. The administration is much simpler. Because you don't have to get up to the upper track. It's bladder. So it's a really simple procedure that can be done in the office, and it really fits in the way urologists treat and you don't need the special equipment. So we have the potential at UroGen to unlock a significant opportunity. And most importantly, as I said, really drive advance for patients with these diseases. What you see here is the $5 billion plus in total is both the -- 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. So 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. So 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 the -- what we have, the infrastructure that we have in place. We had 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 $120 million private placement. So thank you very much to those of you who are here. This was a very telling for us, because we had partners coming to us, saying, we want to work with you. We want to -- we believe in what you're doing. And I think that you'll -- the diligence that they did around our company, around the product, around the opportunity is testament to the true opportunity that we have here. And 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 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 approval as soon as possible. So with that, I'm going to turn it over to Mark to introduce our panel physicians. So thank you. Thank you very much.

Thank you, Liz. Imagine when 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. And 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. So without further ado, Dr. Chamie.

Thank you, Mark. Thank you, Liz. You guys can hear me okay in the back? Great. So I was talking to Arie a little earlier. I first was -- my first encounter with UroGen was about 13 years ago, I was a fellow at UCLA. And 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." And 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 as a doctor and Arie Belldegrun, obviously is Arie Belldegrun. And so he's truly a visionary. And so, I do not envision the data to be this strong many years later. So congrats to the UroGen team. So as the Director of the bladder cancer program at UCLA, I see a significant number of patients with bladder cancer. So on my typical clinic day, I do 15, 16 cystoscopies. I see about 60 patients. I'm instilling chemotherapy. This is a population that has -- that suffers a significant amount from this disease. And so 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. And we follow those patients out for 5 years and found that only 1 out of 7 patients was alive 5 years later without a recurrence or progression. So this is a cohort that suffers from significant co-morbidities and they have competing risks and taking these patients to the operating room puts these patients at risk. So Slide 1 -- go forward. There we go. So bladder cancer is highly heterogeneous, right? So when we talk about bladder cancer, we tend to talk about grade and stage. Those are the 2 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. And we also look at grade, we look at tumor size, location, multi-focality, and that's how we develop risk of disease. But more importantly, as physicians, we have to look at the age of the patient and their competing risk to determine whether this is someone who want to operate on or not. And so the AUA has developed some nice stratification tools, and we use those to stratify patients as either low risk, intermediate risk and high risk. And 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. Now this intermediate risk cohort that undergoes surgeries, as surgeons, we think we can go in there and we can completely resect these tumors, and we feel confident in our reception. But we oftentimes don't realize the implications of what we do. So this is a study that we published using real-world data from Kaiser. So 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 using serum Medicare data, because sometimes patients get care outside of their vicinity and it goes unrecognized. But in the Kaiser system and in a closed system like that, you're able to capture the universe of that patient's care. And what we found was that the adverse events within 90 days of the TURBT is 33%. TURBT is the most complicated outpatient surgery we do in medicine. And 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 pings these patients. The recurrence rate and the progression rate, now 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. And there was a Scandinavian study that actually looked at the patients who undergo multiple TURBTs. And what they found is that those who undergo 2 to 4 TURBTs have a significantly increased risk of dying overall. So 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. And it's not surprising to see a higher mortality rate from it. And we think it's due to the fact that these patients are getting anesthesia, the risk of the complications and the lifelong surveillance in treatment monitoring for these patients. Now 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. And 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. And obviously, we talked about OPTIMA, the OPTIMA trial, 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 2 years, so 24.4 months. So 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. And 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. So Mark, thank you.

Karim, thank you very much. Great setup. And 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. So, 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. So we're going to review the top line data results for the 2 Phase III 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 IIb 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 3 months and really quite significant durability of response data. The ATLAS study, which is a Phase III 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 going to 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. So we'll have both of those available to share today. We'll begin with the ATLAS study. So 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. So 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 2 key secondary endpoints as well. The first was a complete response rate at 3 months. So this is for patients who received topical chemo-ablation alone comparing those patients to surgical resection, how do they do with the first evaluation that we do at 3 months. And that's traditionally the time line in which we reexamined the bladder with a camera called cystoscopy and sample the urine called cytology. And that's really our first evaluation across the board for urothelial cancer when we're looking to see if there's a complete response. And then for those patients that were complete responders, we want to determine how long did they have a durable response with this agent. So we look at those patients who are complete responders at 3 months and then follow those patients forward until they have 1 of those events we described earlier, either recurrence, progression or death. And 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. And 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. And 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 and 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 was performed to confirm low-grade disease. A urine cytology samples of the urine to ensure there's no high-grade cells or cells coming from the upper portion of the urinary system, and we just use a radiographic testing as well to confirm that the disease is only in the bladder. Patients were then randomized 1:1 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 catheters are removed and the drug is administered. Patients come once a week for 6 weeks. It's the same way we've been using BCG for 4 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 chemo-ablative treatments, patients were then assessed at 3 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, a patient would receive a 4-quadrant 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 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 for equivalent between the 2 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. And so the types of things that we see are the type 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 the study drug. And in terms of serious treatment-emergent adverse events, these rates are really quite low across both arms. So in the group that received study drug plus or minus a TURBT, the rate was 1.4% for a serious treatment-emergent AE. And then the TURBT Alone group, that was 0.8%. So again, exceedingly low significant serious adverse events. So this is the primary outcome which is disease-free survival. And I think the takeaway here is that we see a significantly higher rate of patients with some event. And 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. So there's a 55% reduction in risk 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. And again, these patients experience a durable, consistent reduction of risk across all 3 parameters of recurrence, progression or death in this intention to treat population. When we look at complete response rate at 3 months, recall all patients are going to undergo a 3-month cystoscopy with a biopsy if needed, and this is the initial response to just the chemo-ablation Alone versus a surgical resection. And 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. And 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 conference 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 3 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. And here, the hazard ratio is 0.46. So there's a 54% reduction in risk of recurrence, progression or death in patients who received study drug Alone with no surgical treatment compared to those patients who have to go to the operating room, be put to sleep and had a resection. Again, the non-surgical option here is superior in terms of the duration of response. Again, the Kaplan-Meier curve illustrates again the natural history and the magnitude of this change between the 2 study groups. Again, the light blue here is the UGN study drug Alone without resection, and in the blue is the TURBT group Alone. And these are for patients who had a complete response. So 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 with surgical resection. So ENVISION is our Phase III single-arm study, same study protocol. The primary endpoint here is that 3-month complete response rate. So again, the cystoscopy at 3 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. And that will 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. So for ATLAS, those patients that were allowed could be de novo tumors, patients who had no prior history of tumor, but had either multifocal tumors or a large initial tumor. For ENVISION, the patient population are specifically patients who have had a prior diagnosed low-grade tumor. So by definition, every patient ENVISION is a recurrent patient. And so this study cohort really saturates that out in the cohort a bit more. It's a single-arm study. So the demographics and baseline characters are typically what we see in patients with low-grade intermediate risk non-muscle invasive bladder cancer. And again, just to remind you, the mean age is 75. Most of these patients are former smokers. There is 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 3 months potentially for their disease. So again, a very important study population for us to try to minimize surgical risk. Treatment AEs and safety profile very similar to see in other studies. And really the takeaway slide is that for this patient population of recurrent patients at 3 months who had a treatment of UGN-102 Alone, and this is 240 patients, we see a complete response rate with no surgical resection of 79%. And that really is something that is truly paradigm shifting in surgical management. We, as urologists, we 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 resection in the office, in our cancer centers. But to have someone who undergoes no surgical resection and almost 4 to 5 patients will have a complete response at 3 months. And with pre-existing durability, that seems quite excellent, this is an 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. I'm sorry, last thing I would just say for ENVISION because it's important that durability is going to be important. Those data will result in 2024 with a planned NDA submission to follow.

To quote another dead fan 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. And you have met 2 of our panelists. I don't know if I can get this to advance. I need 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 and it is the FDA that determines safety and efficacy. So obviously, we are talking about the use of this drug in the context of clinical practice, but it is not approved. And 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. And to that end, we will have a, 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. But 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 joining us today, who is Associate Professor of Urology at NYU School of Medicine in New York, and Dr. Trinity Bivalacqua, who is a Professor and Director of Genitourinary Oncology in the Department of Urology at the University of Pennsylvania. And so without further ado, we're to be click or go. Okay. Well, since I know what the first slide says, let me start with that. Katie, that one's working. Okay. So what do you think of the data?

Yes. So I think this is exciting. As a practicing urologist, is to find something that could potentially change our practice. If we're talking 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. Yes, it's 1 of the most common procedures that a urologist does, urologic oncology does. But it's probably not good enough, right? We need something else because these patients are recurring. So I think it's very exciting.

Trinity?

Just I was sitting in the back, and I was thinking -- when I -- when we're looking at this data is that you realize we are going to have to train a whole generation of urologists differently if this gets FDA approval. I mean, it is going to change everything potentially. And I was thinking myself, could you imagine telling your residents, we're actually not going to do surgery. We're just going to put some stuff in the bladder, and we're going to potentially change this disease course.

Well, so okay, you anticipate something that Sandip said to me as we were getting ready for the program. So is this going to take surgery away from urologists? Does that matter?

So it's interesting. So I was in academics and I'm not a community-based practitioner. This is a disease we see throughout the community. This is generally going to be seen by every urologist. And so there's people who are concerned that, oh, you're taking away a surgeon's bread and butter. They're not going to do as many resections. We have been practicing to minimize reduction in resections for 40 years. Every patient who gets PCG is to reduce recurrence in surgery. Every patient who gets intravesical chemotherapy is to reduce recurrence and surgeries. Nothing has numbers like this, in terms of doing it. And so 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. I'm not sure that's going to be possible. But let me try, Karim, do you agree paradigm changing? Isn't that too far, is that out of reach?

So I think the UGN-101, the JELMYTO was paradigm changing, and we didn't realize it. We as urologists don't really think of these drugs as chemo-ablative and chemo resection. That's a term that was passed on to us. And I think UroGen was really innovative in bringing the idea of chemo resection or chemo-ablative therapies. Obviously, the idea of chemo-ablative maybe is not novel in this study, but obviously, the data is pretty significant. And I think this is -- I think the data speaks for itself, and I think it's going to be able to change how we practice.

Speaking of the data, let's talk about some of the data. So 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 Sandeep presented this morning in ATLAS and Envision. And this is, as Katie was pointing out, 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're thinking about training resins. What does this say to you?

Yes. So I think 1 of the things as urologists, we're -- so 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, so but this is actually 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 and would take -- give us an opportunity to prevent patients from going to the operating room where unfortunately, we, as urologists, cause significant morbidity. And I think it's all due to the -- essentially the innovative formulation of this drug in delivering chemotherapy, in this case, Mitomycin C.

So you open the door, I got to ask Karim, because he was thinking about this. When we talked about it last night, mitomycin in water. How come we don't just use mitomycin in water here?

Well, 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 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 see 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. And what they found was that those patients who get aqueous mitomycin C, plus or minus TURBT did know better than those who got TURBT Alone. And 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 plus TURBT compared to TURBT Alone. And if you -- I know you're comparing apples to oranges here with 2 different trials. But those that got aqueous mitomycin C plus or minus TURBT did very similar to the TURBT Alone arm in this trial.

So takeaway is, there is something special about UGN-102.

There's definitely some special sauce in 102 plus or minus TURBT.

So 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. So these are patients who received either only drug or only surgery. Sandip, what do you think?

Yes. So again, I think this really illustrates the dark blue line of TURBT Alone really illustrates the natural history of this disease. So 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. And so a 66% reduction in risk of recurrence and progression is significant. And 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 after 3 months, because they don't recur quite as frequently as with TURBT Alone. So 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 will hopefully once approved, to get into the hands of urologists, but it's going to not just change how we treat upfront, it's going to change how is this surveillance going forward.

Does this tell you anything different or confirm any suspicions you might have about the biology of this disease? What does this say to you?

Yes. So this is one of the few trials we heard, 1 of them previously, but that looks that 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. And thankfully, these are recurrences, not necessarily progression. And what this also tells me is that if you use an agent, a therapeutic agent that is able to cut 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 hear it from us over and over again, but that is going to have a direct impact on patient care, but more importantly, their quality of life. Because the people that we suffer from taking care of and they're suffering, and we are actually suffering with them. People that were 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." That gets old. So this could potentially direct...

And he just told me that he is going back to PENN today to go back and to look at someone's bladder to wash out blood clot. I mean, this is something we see in patients.

So Katie we been overstating patients -- 2 patients for years the benefits of TURBT. Does this tell you something about or assumptions about TURBT that might not be true?

Yes. I think it probably absolutely does. I think at the gut of us, we've probably thought this for some period of time. But like Trinity mentioned that we've never really followed these patients to see, how direct those recurrences are. But the patients are also out there asking for this. right? The patient that I scope yesterday, right? And she says, "Oh, we just did this 3 months ago, and now these tumors are here again. Isn't there anything else that you can do?" I don't mind, right? It can have complications with TURBTs, and do, but to go to surgery, she takes off work for the whole entire day. It impacts her economics. It impacts their whole entire family, her life, right, a vacation day from work, so many other things. And then she says, okay, and then I'll come back and then what? I see in 3 months, and we probably do this again. Right? Because she has gone down that route. So 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 a 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 knew. And remember, ATLAS had patients who were newly diagnosed as well as those who were recurrent and had, had a prior history of tumor. It's pretty obvious that this is something that everybody on the panel has already in one way or another mention would be useful in patients with recurrent disease. But does this say there is also a use for patients who have a new presentation of tumor. Sandip, what do you think about that?

It's really interesting. And 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 subside that way. The study was done in intermediate-risk patients. I mean, that is the study cohort. And I can tell you, I put a patient on study, which I knew probably had no chance of being successful, but the patient, he's a military veteran, is in his 60s. He's had recurrent tumors for 5 or 6 years, he probably has 40 to 50 tumors in the bladder. And to give you a sense, that would take us 2 to 3 hours at maybe multiple different operations to try to clear this patient and even ergonomically we can reach it. So I have never cleared the patient in 5 or 6 years. I'm basically triaging his bladder, coming back 3 months later, doing it again, trying to avoid bleeding episodes. And so I put this patient on study. And I look back into 3 months, and he went from probably 50 to 55 tumors down to about 4. So technically, the patient was not a complete responder. I then resected that patient and he has since been disease-free for the first time ever. And 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 him 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 3-month complete responders. And I think that's how we're going to use it in practice. I think we're going to find a way to keep patients out of the operating room or to minimize what we have to do in the operating room.

Thank you. Katie?

You maybe think of something, how there's all these technologies, and so much research has gone into enhancing our eyes for doing cystoscopies, right, and 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? And so 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, they just hasn't been good enough.

Yes, I was going to 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 -- if you actually -- I'm not going to try to say this, but if you're going to extrapolate this out into the community where the average urologist treats maybe 1 bladder cancer or 2 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 dealing with the control arm of a really good surgeon thinking that they can resect everything. And I think if you extrapolate, you find even a greater difference there.

Yes. I'd like -- so obviously, the data is -- it is what it is, and it shows that this is an effective agent. 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 going to appear to be 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 to respond. So I think when I think about IR non-muscle invasive bladder cancer, it gets risk-stratified, right, into very high risk of recurrence. Once again, these are not people that progress and those that 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 6 intravesical installations, you may need less. What is the role of maintenance? I mean, there's so many things that I'm thinking about 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?

Yes. I think that's a great question, right? And I think Sandip has mentioned it several times. This intravesical installation is not new to urologists. We're extremely familiar, right? We love 6 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. And 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. So I definitely think in comparison to even JELMYTO, the adoption in just routine practice seems much simpler.

So you're working in an academic center. Sandip, tell us about how this might fit into community, what's from your perspective?

Yes. So we're a group of 26 urologists, which is a very large practice, probably largest of the 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. And so 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. And again, to me, this in our practice is just to grow the [ pie ] opportunity. This just allows me to do something else and see a new patient that I might have had to wait another week or 2 weeks to see. So again, reimbursement is going to be important, right? That's going to be important for any treatment that we give. But again, this has got a very easy and nimble way of giving it. So I think as long as those are sort of a reasonable commensurate reimbursement for the time, I think this is not going to have much in the way of obstacles for implementation.

Interesting. So urologists won't be pining away for these patients, and they won't be missing the surgery, so find something else to do.

Well, I think that when -- I treat primarily bladder cancer. So this is what I do for a living. And if I had patients who didn't go on to TURBT for the intermediate risk, I would not -- obviously, I wouldn't skip a beat with regards to those patients. But I think the perception that this is going to take away part of their income, I think, is a misconception. I think, when a patient comes in, so when we -- in surgery, we kind of value our time in the operating room or in the clinic based on work RVUs. And a typical TURBT gives you anywhere from 2 to 7 RVUs, but most of the patients are in the immediate risk group tend to be around the 2 to 5 range. Installations in the clinic over a 6-week period gives you about 12 RVUs, which is about 2.5x what you would get from just doing the surgery alone. So the economics make sense for the urologist. And I think in the long term, it's going to benefit the patients more.

Yes. 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, they use prostate cancer active surveillance is going to take away radical prostatectomy, did it? Absolutely not. And you have more people that are showing up. And ultimately, those people would active surveillance, guess what, they need surgery or radiation. So these things, we see it every decade, something like this comes up.

So speculating 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 we are excited about this, but patients are going to be excited, right? We talked about in one of those first slides how recurrent this is. People are undergoing 5, 10 TURBTs over the last 10 plus years of their lives. Every 3 months coming to see us in clinic and go through these things. So the first inkling that they hear something, their ears are going to perk up, right, because they're asking us every 3 months. So now what? And I say, "Well, I'll see you in 3 months. Have a nice vacation or whatever it is." And so 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. 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.

And we're going to still be doing cystoscopies. We still have to do surveillance on the bladder, right? So this is not eliminating a cystoscopy. What this eliminates is TURBT, right, that eliminates anesthesia, eliminates taking you off a blood thinner. It eliminates all the things that are involved in a more intensive operation, flexible cystoscopy in the office, which takes each of us 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 had a somewhat checkered record with regard to adopting Level 1 evidence and data in general into practice. Any advice for UroGen regarding how to talk to urologists about the value of this...

Get on the guidelines. Get on the guidelines, on the AUA guidelines, it will be utilized.

Yes. Any other thoughts?

Ways to talk about this?

Yes, yes. I think, 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. And it's a reminder that these patients have had TURBTs. It's not -- 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 very multifocal tumor and it decreases in amount like in Sandip's patients, then that patient then went on to a TURBT and had a complete response thereafter. And so it's a very mixed bag, and I think that we very much have to approach it that way with the surgeons, urologists out there.

I mean, there was a paper that we wrote about maybe 10 years ago that looked compliance with guidelines, and we found that the compliance was terrible, right? [ Ed Messing, ] who ran the SWOG trial, where they gave perioperative gemcitabine compared to TURBT Alone, he was able to accrue like gain busters in the clinical trial. But once the trial was done, patients getting perioperative gemcitabine tanked. And 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. And I think doing a trial like the ATLAS and ENVISION trial is truly a study that's feasible that urologists will adopt and provide for the patients. So I think the most important factor here is feasibility.

Yes. I mean, Karim, I hate to push back, but I'll push back. I mean, using perioperative chemotherapy after TURBT, that's variable, right? I mean, the patient may have hematuria, the bladder is thin, you name it. This is a therapeutic agent for a disease state that is safe. And it is easy to do because urologists are used to doing it. And nowadays, when you, unfortunately -- I shouldn't say that, there are other oncologists, besides urological oncologists that are managing non-muscle invasive bladder cancer. So what they're doing is looking at the NCCN guideline, looking at the AUA guidelines as to what are our recommendations. So I studied 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 had to finish up, I'm going to ask you 1 other thing. And then we touched on it a little bit, but just to get the concrete statement from you. The neoadjuvant paradigm. We talk about it all the time in muscle-invasive disease. What do you think -- how do you think it will play in non-muscle-invasive disease? Trinity, do you want to start off with that?

Yes. I think, that it will be a lot of education and being able to educate and in part knowledge to neurologists that this is a concept that will work. I think, urologists are very much early adopters. You may look at the surgical robot. I mean we have adapted the robot quicker than any other professions. So I think if you show them the data, I keep saying this, if the durability is good and from the Phase III trial and you show the data, I think urologists are going to very much embrace this for many reasons.

Katie?

Yes, I was going to say, I think it has to do with 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 in my practice that I get referrals in from 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. So it does come into play in that situation that you could really downstage or decrease volume of patients and make them more resectable at TURBT at that point in time. So I think that, that is the perfect patient for neoadjuvant therapy.

I think the reality is that almost 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 are partial responders, thank you. Right? But I wouldn't look at anything as a new adjuvant paradigm. This is a treatment that has incredibly high rates of complete response. And so 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, due to more definitive surgery. Here, like Sandip was saying, 79% of patients never go on through that definitive surgery, because the treatment was able to chemo-ablate. So I think this is different. And I think, 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 and 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 second, because we're going to move into a question-and-answer session. And 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. And 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 neurology. Everything else is kind of incremental improvement, interesting scientific observations. But with these data, we actually are looking forward to a different way of caring for patients. So UGN-102 is not just a drug. It is, as Karim has 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 [ Bernie Fishers ] move to take us away from radical mastectomy to lumpectomy and radiation therapy in breast cancer. This is that big change in the way we think about this disease. So I hope that's come through clearly. And with that, let me invite Liz Barrett back up, so we can do a Q&A. And let me ask the panel to stay here in case there are questions for panel members.

Thank you. Thank you, Mark. What we're going to do is so 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 we'll join you for a management Q&A. And hopefully, maybe we could talk Arie into coming up and joining us as well. So any questions you have for the physicians for us?