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

Hello, and thank you for joining us today for UroGen's Spotlight Event. We will be making certain forward-looking statements during this program. These may include statements regarding the success and timing of our ongoing and planned clinical trials, data presentations, regulatory filings and future research and development efforts, among other things. These forward-looking statements are based on current information, assumptions and expectations that are subject to change. Please review the forward-looking statements slide being presented, which will also be accessible on our website in the Investor Relations section at the conclusion of this presentation and the full description of potential risk factors found in our latest SEC filings. You are cautioned not to place undue reliance on these forward-looking statements. UroGen disclaims any obligation to update these statements, content from today's presentations as well as a video replay on our website. Following this pre-recorded session, we will host a live question-and-answer session with management. Thank you again for joining us as we share with you our vision for the future of UroGen.

Welcome to UroGen's Spotlight Event. My name is Dr. Arie Belldegrun and I am the Chairman of UroGen Pharma. Since its inception, the vision for UroGen was to become the center of and magnet for innovations in urology and for urologists, specifically in the highly needed area of urologic oncology. My fellow urologists know something that is often not widely understood. Urology (sic) [ UroGen ] has quietly been a leading innovator in the treatment of not only urological cancers, such as kidney, bladder and prostate cancer, but in the treatment of other solid tumors for decades. And now more than ever, there is transformative shift underway in the field of urology. A shift that makes urologists increasingly prominent in patient care as they embrace therapeutic intervention to provide enhanced patient satisfaction and ensure they remain as the primary gatekeepers for their urologic oncology patients. And UroGen has the potential to become their biggest partner in this transformation as it offers a novel approach that is uniquely suited to the way urologists practice medicine. Much of modern surgery is about finesse and the ability to leverage technology to minimize harm. UroGen's RTGel utilizes molecular finesse. The RTGel platform with the elegance of the reverse thermal gel allows the power of its therapies, both approved and those in development, to stage an attack on cancer by non-surgical means. UroGen's novel approach follows in the tradition of urological innovations using multi-model integrated and novel treatments to potentially improve outcomes while caring for patients. Each and every one at UroGen merely represent the thousands in our field around the world who recognize that urologic oncology offers an incredible opportunity to test the limits of immunotherapy for the treatment of solid tumors. Urothelial cancers and bladder cancers specifically are more easily accessible and there is limited competition even though we have an aging and growing patient population. What we learned from the therapeutic treatments for these types of cancers open the door for even greater possibilities where dwell time is key, from brain cancers to bladder cancer and everything in between. This means that the opportunities for UroGen go well beyond uro-oncology. It is just beginning as it helps to shape the future and ushering a new era for this field. UroGen is committed to empowering urologists and their offices to bring better options for patients, targeting some of the most prevalent cancers that, much like the specialty itself, are often left out of the limelight. And with UroGen's help, this specialty now has a new home for innovation and an opportunity to take center stage in the greater medical community. Thank you very much. [Presentation]

Hello. I'm Liz Barrett, CEO of UroGen Pharma. Thank you for joining us today. When we set out to define the mission of this company, we had patients like Kathy in mind. Patients who are faced with the enormity of a diagnosis of low-grade upper tract urothelial cancer. But also they understand is there are limited treatment options that can help them fight this disease. For decades, patients have received the standard practice, which was surgery to remove the kidney. It's because of these patients that UroGen exists. We believe that patients deserve better. How do we do better by patients? By striving to fundamentally change the way urologic and specialty cancers are treated. While the field of oncology as a whole continues to forge new treatments, advances in urothelial cancers have historically been limited. However, with innovation and delivery technology from UroGen, there is now hope that the treatment paradigm can shift from surgical care and disease management to therapeutic ablation of certain tumors in urology and adjacent hard-to-treat cancers. The catalyst for this shift has been UroGen's RTGel reverse thermal hydrogel, a proprietary sustained-release hydrogel-based technology that has the potential to improve therapeutic profiles of existing as well as new drugs. UroGen's sustained-release technology is designed to enable longer exposure of the urinary tract and other epithelial-lined space to medications, making local therapy a potentially more effective treatment option. Jelmyto, the only FDA-approved non-surgical treatment for patients with low-grade upper tract urothelial cancer, or UTUC, was the first of our medicines to demonstrate this paradigm shift towards more innovative non-surgical options for patients. Jelmyto uses our novel RTGel technology to deliver the chemotherapeutic agent mitomycin to the upper urinary tract. We believe this is the first of many innovations to come. The potential for breakthrough treatment has not stopped with UTUC. Bladder cancer is the fourth most common cancer in men and the 11th most common cancer in women, accounting for almost 7% of all cancer cases. Among the 80,000 estimated newly diagnosed cases of bladder cancer in the U.S. each year, nearly 75% are non-muscle invasive bladder cancer. While the survival rate for low-grade bladder cancer is high, the current treatment is invasive and highly reliant on the resection of the bladder tumor, with 50% to 70% of patients experiencing recurrence within 5 years of surgery. Statistics such as these demonstrate by the numbers why patients deserve better options. Options that don't have to involve invasive surgery. That is why we are developing UGN-102, a locally delivered treatment similar to Jelmyto that utilizes our proprietary gel to deliver a customized combination of RTGel and mitomycin designed to be an alternative to invasive surgery. UGN-102 is currently being evaluated in a Phase III trial in patients with low-grade intermediate risk, non-muscle invasive bladder cancer. We have worked diligently over the past few years to educate the FDA on the unmet need in non-muscle invasive bladder cancer, particularly focused on the intermediate risk patients that endures multiple recurrences. The FDA understands there needs to be better options for these patients, as demonstrated by our news today. Based on our ongoing discussions with the FDA, UroGen will conduct a single-arm study of UGN-102, similar to our Phase II study that can be the basis for an approval in this patient population. Dr. Mark Schoenberg, our Chief Medical Officer; and Dr. Elyse Seltzer, our Chief Development Officer, will discuss this in more detail, but this update is a significant advance for patients and for UroGen as it provides greater certainty on timing and probability of success. Additionally, we have identified other areas in bladder cancer that we believe can benefit from treatment with UGN-102, and Elyse will share more on our life cycle plan. As our near-term plan advances on schedule, I want to highlight our pipeline and vision for our RTGel technology and its potential to change treatment paradigms in specialty cancers. Our pipeline reflects our vision for the future to address outstanding medical needs by leveraging our expertise in local delivery, with methods that have been proven successful in recent years, such as harnessing the immune system to fight solid tumors and adapt them to treat urologic and specialty cancers. With our third and fourth pipeline opportunities, UGN-301 and UGN-201, we are expanding into other non-muscle invasive bladder cancer patient populations, including high-grade disease where patients face disease progression, which may in turn lead to the development of metastasis and an increased risk of death. We are exploring the therapeutic value of locally delivered immunomodulators, such as UGN-301, using our RTGel platform, which enhances time on target of the therapeutic agent. UGN-301 or zalifrelimab is an anti-CTLA-4 checkpoint inhibitor and belongs to a class of potent immunomodulator drugs which when administered systemically have led to improved outcomes in patients suffering from dire illnesses, such as metastatic melanoma. Unfortunately, the systemic administration of anti-CTLA-4 is associated with higher rates of dose-limiting toxicity. Based on encouraging non-clinical data, we are now studying the local administration of UGN-301 in a variety of settings, both as monotherapy and also in combination with other immunomodulators, including 201. UGN-201 is a proprietary formulation of imiquimod, a toll-like receptor 7, or TLR7 agonist, which is known to elicit immune response to bladder cancer. In collaboration with MD Anderson Cancer Center and the Nobel Prize winning scientist, Dr. Jim Allison and his team, we are evaluating the potential synergistic immuno-oncology effects of UGN-301 and UGN-201 in high-grade non-muscle evasive bladder cancer. Together, these agents could activate both the innate and the adaptive immune response. We are planning to initiate a Phase I clinical trial for this combination in early 2022. We plan to continue combining UGN-301 with various immune modulators with the goal of developing the optimum medicine or medicines for these patients. In addition, we are excited about work by collaborator, Professor Dr. Wim Ceelen, Department of Human Structure and Repair at the University of Ghent, who is evaluating the effects of imiquimod, our TLR7, and has already established mouse models of peritoneal metastasis of colorectal carcinoma. Building upon what we have learned from our success in treating urinary tract disease, we plan to explore other cancers that could benefit from local, sustained-release treatments such as bile duct, rectal and cervical cancers. Going forward, we will continue our focus on fundamentally changing the treatment paradigm for some of these devastating cancers by working and aspiring to deliver better medicines to patients in ways that have never been done before. As Arie mentioned earlier, there's a transformative shift underway in urology and other specialty cancers to attack cancer cells by non-surgical means. UroGen is pleased to be a partner in this transformation to embrace therapeutic invention to shape the future of patient care. Now I would like to turn it over to Mark to discuss UGN-102 and how UroGen is working to leverage this technology in order to address unmet medical needs in bladder cancer.

Thank you, Liz. Hello. I'm Dr. Mark Schoenberg, Chief Medical Officer of UroGen Pharma. As a practicing urologist, I'd like to take the time today to discuss the current unmet medical need for alternative treatments for patients with bladder cancer. Dr. Seltzer will then provide an exciting update on our discussions with the FDA regarding our Phase III program in low-grade, intermediate risk, non-muscle invasive bladder cancer. It may be useful to start out by explaining the anatomy of the organ we're treating. The urinary bladder is a hollow organ located in the pelvis, the purpose of which is to collect urine excreted by the kidneys and then to expel urine during normal voiding. The bladder has a complex nervous system and a multilayered wall. The innermost layer is called the urothelium and it is in constant contact with urine. This epithelial surface is the origin of over 90% of bladder tumors. The underlying layers provide support for the urothelium and the layer of muscle produces bladder contraction at the time of voiding. Cancer cells running from the urothelial lining of the bladder are identified as low and high grade. Low-grade tumors look very similar to normal urothelium, whereas high-grade cancer cells look very different, with irregular borders, abnormally shaped nuclei and other features that readily distinguish these cells from the normal lining of the organ. To orient you regarding the investigational usage of UGN-102, we're focusing on a large patient population that has low-grade, intermediate risk non-muscle invasive bladder cancer. This is a group of patients with tumors that have a very limited capacity to invade or spread but a high likelihood of recurrence following standard treatment. It's estimated that intermediate risk disease represents approximately 25% of newly diagnosed bladder cancer in the United States and the current standard of care includes transurethral resection. Patients with low-grade, intermediate risk non-muscle invasive bladder cancer typically experience multiple tumor recurrences, and consequently, under the repetitive surgical treatment to control this disease, repetitive surgeries associated with specific risks that include bleeding, infection, injury to the bladder and the need for prolonged catheter drainage. A recent study from Denmark suggests that the repetitive TURBT is independently associated with an increased risk of death. UroGen is developing UGN-102 as a first-line, non-surgical alternative to repetitive resection. UGN-102 is a specifically formulated reverse thermal gel containing mitomycin. When cooled, UGN-102 becomes a liquid and can be instilled into the bladder using a urinary catheter under local anesthesia. As the instilled liquid warms the body temperature over a period of 1 minutes to 2 minutes, it becomes a semi-solid gel that, while not interfering with normal voiding, slowly releases mitomycin over a period of 4 hours to 6 hours. As the gel disintegrates, it is removed from the bladder by normal urination. Data from our UGN-102 clinical development program suggest that chemoablation with mitomycin may obviate or delay the need for surgery in some patients. In addition, the safety profile of UGN-102 appears manageable in clinical trials. For an update on our clinical development program, I'm joined by Dr. Elyse Seltzer, our Chief Development Officer.

Thank you, Mark, for the overview on UGN-102 and low-grade, intermediate risk non-muscle invasive bladder cancer. As Mark mentioned, we have a robust clinical development program for UGN-102 which includes a Phase III study called ATLAS, which is designed to compare the long-term disease-free survival of UGN-102 to surgery. I am here today to provide you with an update on the ATLAS trial and to discuss exciting next steps for the development of UGN-102. As Liz mentioned earlier, we have continued to have a dialogue with the FDA regarding our belief that there is an alternative approach to demonstrate the efficacy and safety of UGN-102 in the low-grade intermediate risk patient population. We will be initiating a new study of UGN-102 with what we believe is a more streamlined design for assessing the clinical value of UGN-102 in low-grade intermediate risk NMIBC patients. And as such, we are suspending enrollment in the ATLAS study. As you recall, ATLAS required us to compare UGN-102 against surgery, which is highly unusual. The new Phase III trial will be a single-arm, multinational, multicenter trial evaluating the efficacy and safety of UGN-102 as primary chemo-ablative therapy in patients with low-grade, intermediate risk non-muscle invasive bladder cancer. This design will be very similar to our Phase II OPTIMA study in that the patients will have the same clinical characteristics, the same treatment regimen, the same assessments and qualitative follow-up, with significantly fewer patients than ATLAS study required. Although we will not continue to enroll patients in ATLAS, we will continue to follow patients who have already been enrolled and their data will be invaluable as we continue to learn more about the role of UGN-102 as a primary therapy in the treatment of low-grade, intermediate risk disease. We are grateful for the patients and the investigators who have participated in the ATLAS study to date, and we will work with these sites as they follow all ATLAS enrolled patients as they continue their participation in the trial. For the new Phase III trial, study participants will receive 6 weekly intravesical installations of UGN-102. The planned primary endpoint is the complete response rate at 3 months after the first installation and the key secondary endpoint will be durability over time in patients who achieve complete response at that 3-month assessment. Another clinical benefit of this new design is that it will be based on time to an event. This will give us greater certainty surrounding the timing and duration of the study. This design and assessment are aligned with the Phase III study that provided sufficient evidence for FDA approval of Jelmyto for the treatment of urothelial cancer of the upper tract called UTUC. We have achieved consistent results with this design in the past and we feel optimistic that it will likely increase our probability for technical and regulatory success for UGN-102 in patients with low-grade intermediate risk disease. We anticipate enrollment for the new trial to begin the first half of 2022 and enroll approximately 220 patients across an estimated 90 sites. We anticipate enrollment to take less than a year and submission to occur in 2024. Patients with low-grade, intermediate risk NMIBC are currently treated with surgery. And in this population, many of our patients undergo repetitive surgical interventions with all of the associated risks, including the need for general anesthesia. One thing that we have learned about treatment with UGN-102 is that administration is very straightforward and leverages a standard and well-established urologic procedure of installation of medication into the bladder via a catheter. Given that the low-grade intermediate risk patient population is generally older and suffers from multiple comorbid conditions, we are seeking to demonstrate that this treatment is sufficiently straightforward so that patients can avoid the need for repetitive visits to a healthcare setting and can receive their treatment at home by a qualified home health professional. The objective of this study is to demonstrate the safety and feasibility of administering UGN-102 for the treatment of low-grade, intermediate risk NMIBC at home. We are currently working with several centers across the U.S., and our goal is to enroll up to 10 patients. As always, our team is working to bring this therapy to patients as soon as possible. This is an exciting time for our clinical team as we navigate the evolving regulatory landscape.

In addition to our work on low-grade urothelial cancer, we are moving forward with a variety of initiatives, both within and outside of urological oncology. As you'll hear later, we have a truly innovative program directed at treating another population of bladder cancer patients with a different but, we think, equally compelling unmet need, namely those with high-grade NMIBC. What we're focusing on could be characterized as next-generation intravesical immunotherapy, but more on that later. In addition to concentrating on high-grade disease, we are also collaborating with academic leaders to investigate potential therapeutic value of our platform as a drug delivery mechanism for treating diseases that require a topical therapy or for which systemic toxicity is a limiting factor in disease treatment. To reiterate what Liz has already mentioned, those diseases could include head and neck cancer, biliary cancer, colorectal cancer, uterine and cervical cancer and peritoneal carcinomatosis. In addition, we have an immunotherapy program with Johns Hopkins University aimed at studying the potential of checkpoint inhibitors combined with RTGel in glioblastoma multiforme, an aggressive and difficult-to-treat brain cancer. We plan to keep you updated as these collaborations progress. We will discuss the current treatment landscape and potential future innovations in NMIBC with experts in the field in just a moment. But before we join them, Jeff Bova, Chief Commercial Officer at UroGen, is going to lead you through the market potential for UGN-102.

Thanks, Mark. For decades, the surgical procedure known as a transurethral resection of the bladder tumor or TURBT has been a standard treatment for patients with chronically recurring forms of non-muscle invasive bladder cancer or NMIBC. With the disease's low-risk of progression and mortality, there has been limited research and alternative options to the multiple surgeries that are often needed. Recent evidence from the literature shows that TURBT may lead to significant postoperative morbidity and an even increased risk of mortality. Consequently, the patients who undergo repeated procedures may be facing serious burdens that can impact every aspect of their life. Urologists are increasingly aware of these challenges and are interested in changing the way they treat NMIBC. But without a definitive alternative, TURBT remains a routine part of patient care. Today, I'd like to talk to you about this patient population. Some of the specific burdens they are facing and our goal to address this unmet need by developing UGN-102 as a potential primary treatment for these patients. Recurrence in intermediate risk, low-grade NMIBC is a pervasive and often underestimated problem. In patients who recur, it's estimated that 68% will experience 2 or more recurrence episodes throughout the course of their disease, a considerably high and frequent rate in contrast to other non-metastatic cancers. Currently, the only effective primary treatment available is TURBT. On the surface, urologists trust in the procedure, viewing it as a logical and beneficial treatment. But the more the procedure is performed, the more it imposes burden and serious risks on patients. A 2020 Danish study by Ericsson et al. even demonstrated that recurrent low-grade NMIBC patients who have had 2 to 4 TURBT procedures experienced a 14.3% increased risk in mortality in comparison to those undergoing only one procedure. Furthermore, both the literature and the preliminary market research revealed that not all patients are good candidates for TURBT. In fact, about 25% are not appropriate for the procedure, whether due to physical factors such as age and comorbidities or an unwillingness to go under surgery. These are patients who could benefit from a new treatment option that does not exist today. Currently, a significant number of patients with low grade, chronically recurring NMIBC need alternative treatment options. Let's take a closer look at these numbers to see who is truly at risk and where the potential opportunity for UGN-102 exists. When we consider newly diagnosed patients, recurrent patients and those unable to undergo a TURBT, we're looking at more than 80,000 patients in the U.S. in need of a new primary option each year, with each group vulnerable to potential serious surgical risks and burdens. Out of the 80,000 estimated cases of bladder cancer per year, approximately 35,000 are low-grade, non-muscle invasive bladder cancer patients, comprised of both low-risk and intermediate risk. These patients face a future of recurrence and additional surgeries. A significant portion of newly diagnosed low-grade intermediate risk NMIBC patients will recur more than once. It is estimated that patients experience 60,000 episodes of recurrent low-grade intermediate risk bladder cancer per year. And for patients on their second, third and fourth round of treatment, the burden of TURBT increases. Furthermore, 20% of low-risk patients are considered unfit or unwilling to undergo surgery. The need is considerable and the risks are serious. So why can it seem like urologists are not aware of the burden associated with TURBT? Well, actually, we found out that they are. In April 2021, we conducted quantitative research to gain a better understanding of the recurrent low-grade NMIBC market, while also tracking awareness in the perceptions of UGN-102. We surveyed 100 office and hospital-based urologists, almost half of whom were high-volume NMIBC treaters. Overall, the research show that urologists are seeing the burdens of TURBT and there is considerable unmet need in low-grade NMIBC treatment. This slide demonstrates recognition of that unmet need. As you can see, nearly 3 quarters of urologists surveyed acknowledge the burden of repeated procedures on their patients. A key area of concern included the potential for repeated trips to the hospital. Compared to other urologic procedures, TURBT is associated with more hospital readmissions. Urologists were also concerned with an impact on caregivers and the impact on a patient's quality of life that, as studies show, decreases with each procedure. Physical long-term risks of multiple TURBTs include bladder scarring and limited urine capacity, which can lead to issues like incontinence, while studies have shown at quality of life, physical functioning, social functioning and emotional health starts to deteriorate after 2 to 3 procedures. While not shown here, it's important to note that over half of the urologists cited medical concerns around perforation of the bladder, general anesthesia and the appropriateness of the procedure for certain patients. Age, tumor characteristics and comorbidities, such as heart disease and diabetes can all increase the risk of complications from TURBT. Not surprisingly, this same research also reveal that almost half of the physicians interviewed were dissatisfied with currently available treatment. So despite how much they rely and trust TURBT today, they still feel the need for better options. When it comes to what physicians are seeking, the research again gives us valuable insight. Most notably, the most frequently mentioned responses from urologists regarding unmet need for patients with multiple recurrences were: a more effective intravesical therapy, a prophylactic treatment to reduce recurrences, less toxicity and side effects than current intravesical therapies or TURBT, non-surgical and minimally invasive approaches and less burdens of administration for patients. Overall, urologists are asking for a treatment that offers robust efficacy, local delivery is minimally invasive and is proven safe for patients. UGN-102 is a primary, not adjuvant, investigational non-surgical therapy for low-grade NMIBC that checks the boxes when it comes to fulfilling the unmet need. UGN-102 works directly in the bladder. Similar to Jelmyto, UGN-102 is a reverse thermal hydrogel that contains mitomycin, though the concentration of mitomycin is tuned specifically for treatment within the bladder. UGN-102 clinical data suggest the potential for durable efficacy. Data from our Phase II study shows 65% of patients achieved complete response at 3 months, and that the probability of durable response 12 months post treatment initiation is estimated to be approximately 73% by Kaplan-Meier analysis. Treatment with UGN-102 was generally well tolerated in investigational studies, with the most common AEs related to the lower urinary tract and reported as mild to moderate. UGN-102 is minimally invasive, non-surgical investigational treatment. It is instilled as a chilled liquid via a standard ureteral catheter. Once it reaches body temperature, it forms a semi solid gel that provides a dwell time of up to 6 hours, allowing mitomycin to chemo-ablate tumors. UGN-102 delivers on ease of administration. It is a relatively quick and simple procedure that can be done in-office, sparing patients the burden of a hospital stay and the risk associated with surgery. When asked in the research, 96% of the urologists surveyed would adopt UGN-102 within 2 years of a potential FDA approval. Currently, though other non-surgical approaches are being investigated, there are no direct competitors to UGN-102. The opportunity is here to ensure that urologists are ready to adopt UGN-102 as a primary treatment option to TURBT. The next step is a provocative prelaunch campaign intended to bring the concerns about the burdens of TURBT to the forefront. What you are seeing may surprise you, but based on our conversation today, our job is to ensure urologists reconsider their reliance on TURBT. The visual concept of the campaign shows a urologist's resectoscope, the instrument that is used in the TURBT procedure. In this rendition, however, the resectoscope transforms into something a little ominous. The campaign then asks, "When does benefit become burden?" This acknowledges that TURBT is an effective standard of care but also challenges urologists to think about the patient types and the long-term management of the disease. It demonstrates how the benefits of TURBT can transform into a serious burden when performed too many times or on the wrong patient. Sharing this story underscores the clinical, physical and psychological burdens of repeated TURBT. It will accompany this imagery to tell the full unbranded story. This approach resonated well with urologists. The imagery was immediately recognizable and it had universal stopping power. Most urologists noted that it would turn heads at a conference and it would tempt them to keep reading if viewed in a journal. With UGN-102, we are determined to explore its potential utility for low-grade NMIBC patients as a better non-surgical treatment option. We're now going to hear from some urologists, what they experience in the clinic and the unmet medical need that exists from their expert perspectives.

Thank you, Jeff. I'm now pleased to welcome 3 distinguished clinicians who have played a key role in investigating the potential of UGN-102 in non-muscle invasive bladder cancer. Before I introduce the panelists, however, I'm required to note that these gentlemen are representing their own views and not necessarily the views of their employer or affiliated institutions. Additionally, they are consultants to UroGen and are being compensated for their participation in today's event. And without further ado, let me introduce the panel to you. First, Dr. Sandip Prasad, a urologist with Atlantic Medical Group and Morristown Medical Center; Dr. Gary Steinberg, Professor of Urology and Director of the Bladder Cancer Program in New York University Langone Health; and Dr. Bill Huang, Professor of Urology and Radiology at NYU and Chief of Urology at Tisch Hospital. Gentlemen, thank you for joining us. And Dr. Steinberg, let me start with you. We're very focused on the treatment of non-muscle invasive bladder cancer. And I wonder if you could describe for our audience the standard of care and the challenges the physicians and patients face in dealing with this disease. What are the unmet medical needs? And from a clinical perspective, what are the opportunities to change the care of these patients, particularly those who are undergoing repetitive surgical intervention using TURBT?

Well, first off, thank you for having me speak. And one of the things that most people don't know and don't understand is that bladder cancer is a very common disease. It's a common disease of the aging process. And it's not only much in the United States, but it's worldwide. And so we see patients in the 70s and 80s that have other medical comorbidities, they're not as mobile, they have other financial considerations and so forth, that come down with or diagnosed with bladder cancer. It's a disease that many times or most often is non-muscle invasive. And it is a disease that can continuously recur within their bladder. More ominously, it can progress and go to other parts of their body and so that it can be a life-threatening disease. The most common presentation is patients who have blood in their urine or they'll have change in their urinary symptoms. Again, this is in an elderly patient population and this symptom, this blood in the urine, can be quite problematic. They can have frequent tumors and recurrences that require frequent visits to the doctor's office; cystoscopies, which is instrumentation of the lower urinary track with telescopes; biopsies, requiring healing from the biopsies, having to have indwelling Foley catheters for a period of time. And so that not only is it a life-changing event and a nuisance for these patients, it also creates a problem for their family members. Because all too often, it's their children and younger family members who have to take a day off of work to bring their loved one in to see the doctor, stay with them while they're having a procedure, drive them home, look in on them and take care of them for a couple of days. So it becomes a considerable problem financially for the patient as well as a considerable cost for health care in the United States and Medicare. Most importantly, we typically treat these patients with treatments where we look inside the bladder and we try to cut tumors out and put medication in the bladder. Despite that, even with high-grade tumors, the more aggressive types of tumors and our best forms of treatment, we still see patients recurring with their bladder cancers 30% or 40% of the time, if not greater. And this is with standard of care therapy. And patients with these recurrent, intermediate risk, low-grade tumors, despite all of the types of treatments that we use, they continue to have recurrent tumors requiring procedures. In a perfect world, we would have patients be able to take a pill, a chemo-prevention pill to prevent the tumors from coming; or more importantly, once they have them, to just note the tumors away. Clearly, we're trying to move in that direction with a number of newer agents which we believe will not only help prevent the tumors from coming in the first place, but also, once to have tumors, to potentially melt these tumors away without requiring surgical intervention.

Thank you very much. And that's a great segue into a question I'd like to ask Dr. Huang. Dr. Huang, you have been very involved in the clinical trials program with UroGen, and in particular with the OPTIMA Phase II trial that was really the first U.S. examination of the potential clinical utility of UGN-102. I wonder if you could talk a little bit about that trial, what you found, maybe the specifics related to the logistics of treating patients in that trial and then the significance of the findings.

Sure. So just to echo Gary, thank you for giving me an opportunity to speak. I was very excited to be a participant in this trial, which is called the OPTIMA trial, which is a Phase II trial using a novel chemo-ablative agent. I think the one thing that we have to keep in mind here, as Dr. Steinberg had mentioned, is that surgery through transurethral resection has been the mainstay of treatment for bladder tumors. And so patients with bladder tumors have to undergo an operative procedure, frequently involving general anesthesia and involves the risks of general anesthesia as well as the risks of surgery itself, including bleeding, bladder perforation, the need for a catheter, etc. So what this trial demonstrated was the ability to use an intravesical agent, or a drug which is instilled into the bladder, and to actually treat or ablate these tumors without any sort of surgical procedure. So in this trial, we selected patients who had what we call low-grade, intermediate risk bladder tumors and treated these patients rather than with surgery, but instead with chemoablation. And so, these patients received 6 installations of this novel agent, UGN-102, and had their tumors chemo-ablated. What we were pleased to see was that 65% of patients had actually a complete response, meaning that when we looked in the bladder 3 months after the installation of the treatment, we noted that they had no residual tumors left. And not only were we pleased to see the success in chemo-ablating tumors, but we also saw a good degree of durability with 73% of patients having a complete response, have a durable treatment response as well 9 months after initiation of treatment or 12 months after starting the treatment. So overall, this was a very, very exciting finding that for the first time we could treat bladder tumors without taking the patients to the operating room and performing surgery on them.

Really exciting, and thank you for that description. I'm wondering if you could expand a little bit on your description of the populations of patients who might potentially benefit in the future. This trial obviously focused on intermediate risk patients, but are there other groups, for example those who either are unwilling or unable to undergo surgeries who might be candidates, as well as potentially other groups of bladder cancer patients who you think might be appropriate for treatment with this type of approach?

Sure. Absolutely. So for this particular trial, the patient population was a select patient group that had a lot of recurrences but had what we consider low-grade disease or disease that is unlikely to progress, to metastasize and lead to death potentially. However, this does open the door to the possibility that this type of therapeutic approach, chemoablation of tumors, can be applied to different subsets of patients with the same problems, being they're old, they're too sick to tolerate surgery or they're simply refusing to undergo major surgery in order to treat their bladder tumors. So this sort of proof of principle that you can treat these tumors by chemo-ablating them opens up a door to a wide variety of different patients that we can consider using this treatment approach.

Thank you. Dr. Prasad, in contrast to our colleagues in academic medical centers, you have a really big community practice. And I wonder how you and your partners view the availability potentially of a therapy like this that could offer patients an alternative to surgical innovation. How will you use this in your practice? How will it get adopted by your partners? And what role will it play, do you believe, in the evolution of community practice for the management of this patient population?

Thank you, Dr. Schoenberg. And I think it's important to include community-based urologists in these discussions. The majority of low-grade bladder cancer in the United States as well as the majority of intermediate risk low-grade cancer is in the community-based setting, right? Unlike advanced disease for bladder cancer, these patients are not typically referred to academic centers, they're typically managed by the diagnosing urologists. In our practice, there's 20 to 25 urologists that see patients regularly, and almost all of them independently manage their own bladder cancer, certainly for low-grade and low-risk disease. So I think again, the impact of this product and products like this on community practice, I think, are very significant. But we've been very fortunate to be involved in the Phase III study, ATLAS, and I've had multiple patients who've enrolled in this study. And I can tell you there's great enthusiasm for this agent by both providers in our practice as well as others in large urology group practices as well as patients for nonsurgical options. Many of these patients are older, as has been previously discussed. Many of these patients have been to the OR repeatedly, whether it's for recurrent disease where they're going under anesthesia several times a; year or patients who had multifocal disease, where different locations in their bladder have been replaced by scarring. These patients are very enthusiastic about having an option that does not take them to the operating room. We've also seen in our community-based cohorts that the use of blood thinners has become more and more prevalent. And again, in our community-based settings, where some of these hospitals are relatively small, taking patients off blood thinners and putting them at potential risk for adverse cardiovascular events or stroke I think has significant bearing on patients and concern for providers and primary care physicians. So I think, again, a nonsurgical option where patients can remain on blood thinners, avoid the scarring and repetitive anesthesia I think has tremendous importance and enthusiasm amongst providers in the community. The reality is that we're pretty well situated to administer these types of agents. We've been giving, in community-based sites, intravesical chemotherapy for years. And so the use of these agents in our offices, in our local cancer centers, I think is easy to integrate. Certainly, we've been able to do that as part of clinical trials in our own practice. But again, I don't think that's a major obstacle in any way as intravesical chemotherapy has been routinely administered. I think again, I found for patients who have been interested in the trial as well as those that I've seen who are interested in the agent, it's really those patients that are multifocal and then are recurrent. These patients have a tremendous experience with the disease. Many of them have had catheterizations and are not averse to that process. And they're really looking for ways to stay out of the operating room and are happy to come to the office for a treatment to replace that.

Thank you very much. And actually, you raised an interesting point that I'd like to circle back to Dr. Huang to discuss. Dr. Huang, you obviously consented patients for the clinical trial and have experienced consenting patients for surgery. What were patients' reactions when you explained the options to them within the context of the clinical trial and what types of experiences do these patients who did participate in the trial convey to you and describe?

Yes. So, it is an interesting point to bring up. This is a patient population that is largely frustrated with the fact that in order to treat their disease, which is frequently recurrent, that they have to go back to the operating room. They have to undergo the repeated procedures. So any opportunity that spares them -- any agent that could spare them an opportunity to not go to the operating room is actually very welcomed by these patients. And so I found it quite easy to consent patients to this because it definitely gave them a chance to avoid having to ''undergo the knife" to treat their bladder tumors. So there was quite a bit of enthusiasm. Almost everyone who has offered it was very interested in pursuing it.

Thank you. Let me close with a question I'd like to pose to each of you, and perhaps we'll just go around the room. I'll go backwards and ask Dr. Prasad first. How do you see the paradigm of treating patients with non-muscle invasive bladder cancer changing?

So I think one of the areas where there's opportunity in bladder cancer and certainly for novel agents is having molecular diagnostics help us to really assess risk of progression, recurrence, as well as response to specific therapies. We've been using these in prostate cancer and have really become the norm with newly diagnosed disease in prostate cancer. And I think in the bladder cancer as well, we desperately need similar tools. The disease is so heterogeneous, tumor response is so variable, I think the opportunity to identify those patients that we know off the bat at the time of diagnosis that will become recurrent or multifocal. Then being able to offer them treatments like this upfront saying that we know the [ nature ] of this disease and we know there's durable options that can keep you out of the operating room, I think these types of molecular diagnostic tools are going to be invaluable as we go forward and diagnose and manage patients with bladder cancer.

Thank you. Dr. Huang, if you had to look in your crystal ball, what would you say is going to be the future of managing this population?

So I definitely think that through this trial and the current Phase III trial, we are really embarking on a very novel way of treating bladder cancer. These patients have what we often call field effect, so their entire bladder's at risk of developing these tumors. And this model of playing whack-a-mole, where we're just going in every so often, we see one, we scrape it out, we see another one we scrap it out, that's going to go by the wayside when we have advancements in medicine. Eventually, we'll have a pill or a drug that they could take. But in the meantime, I think this is the next step forward for moving away from that model and actually treating the entire bladder wall and treating these patients with nonsurgical therapeutics.

Thank you. And finally, Dr. Steinberg, there are a lot of interesting drugs out there being explored by various investigative groups and small companies, but the intravesical approach, as has been pointed out by this panel, is mainstay of urologic practice, do you envision that the intravesical approach is going to continue to be important to urologists in the near future?

Absolutely. I mean I think that bladder preservation is so important to patients and patient population and patient advocacy groups. And I think we also need to strive to find ways where we -- if we're going to intervene an instrument in the urinary tract that we do it as less often or as infrequent as possible. So we clearly need better treatments and we need better intravesical therapies. These are tumors that, by and large, are contained within the bladder. They are not outside the bladder. They don't invade or go to the lymph nodes or into the bloodstream, so we do need local therapies. And the beautiful thing about intravesical therapy is that you can avoid any systemic toxicity. But we have a long way to go to improve our local therapies. Historically, regardless of the types of medications we put in the bladder, they weren't effective because despite them being non-toxic, we really didn't get the penetration or the interaction between the drug and the urothelium like we need to. And clearly, UroGen-102 is demonstrating that by better adherence of the drug to the urothelium for longer periods of time is safe, but more importantly, much more effective. And I think that this is a paradigm that we can -- need to continue to push forward.

Gentlemen, thank you very much for your time and your comments. This has been incredibly interesting and good afternoon. Thanks once again to Drs. Prasad, Huang and Steinberg for the discussion on unmet needs and potential future innovation in treating low-grade, intermediate risk non-muscle invasive bladder cancer. I mentioned earlier that UroGen is pursuing strategies to address the treatment of another form of NMIBC called high-grade disease. This is the form of bladder cancer that has the capacity to invade the bladder wall and spread to other areas of the body. In short, high-grade disease is potentially life threatening. The history of high-grade disease is worth touching on before we meet our next group of panelists because it will help explain how urologists approach this disease and why UroGen became so interested in immunotherapy. In the beginning of the 20th century, scientists in France struggled to develop a vaccine to prevent tuberculosis, a disease that remains a major public health problem internationally today. The drug they developed was a weakened form of a bacterium, Bacillus Calmette-Guerin or BCG. The medicine is still used today to prevent TB and is believed to be a powerful if somewhat nonspecific stimulator of the human immune system. In the 1960s, scientists in the U.S. studying the potential link between immunity and cancer demonstrated that BCG had anti-tumor properties when directly injected into a malignant lesion, such as melanoma. The question was, could the immune system be stimulated sufficiently to cause it to destroy a patient's tumor? In the 1970s, high-grade, non-muscle invasive bladder cancer was still treated with TURBT; and when that failed to control the disease, bladder removal. In a simple-sounding experiment, physicians in Canada instilled an aqueous solution of BCG into the bladders of patients with a form of high-grade disease called carcinoma in situ. This produced remarkable results. The majority of patients experienced complete resolution of their cancer after treatment. And the success of this clinical trial transformed the management of high-grade, non-muscle invasive cancer at the end of the 20th century. And patients who had previously been relegated to a life-altering surgery as their last resort now had an opportunity to control disease with medication. However, while many patients initially responded to treatment, more than half relapsed, typically within a few years. Extended maintenance regimens improved long-term outcomes somewhat, but many patients ultimately require bladder removal to save their lives. Lab research suggests that BCG is a stimulator of both the innate and adaptive immune systems, components of the aggregate human response to a broad range of diseases. But the precise mechanism of its therapeutic action remains a subject of research even today. What the BCG experience showed urologists is that bladder cancer is sensitive to immunomodulation. Scientists like Nobel Laureate Jim Allison of MD Anderson Cancer Center have made a career studying how the immune system interacts with and can potentially be harnessed to combat cancer. One area of particular focus has been on molecules called immune checkpoints, specific proteins that tumors make that help cancer [ slide ] from the body's normal immune surveillance mechanisms. Checkpoint inhibitors are antibodies to these checkpoint proteins which can unmask tumors making them visible to the immune system and facilitating a beneficial response by the body's natural defenses. Although not without side effects since they are administered systemically, checkpoint inhibitor antibodies can produce a variety of side effects that range from mild and manageable to potentially life-threatening and irreversible. Although antibodies to checkpoints have been shown to have beneficial effects in a wide range of advanced cancers, including metastatic bladder cancer, the side effects of checkpoint therapy can significantly limit the use of some of the most potent and promising agents. At UroGen, we've also been intrigued by the potential of immunotherapy for the treatment of high-grade, non-muscle invasive bladder cancer and have pursued a series of preclinical studies to determine whether our proprietary RTGel platform might provide a method for delivering highly potent immunomodulators directly to the bladder surface, thereby avoiding toxicity associated with systemic administration. In the experiments performed in a mouse model of high-grade bladder cancer, we evaluated the direct delivery of checkpoint inhibitory antibodies, such as anti-PD-1, PD-L1 and CTLA-4 to the bladder lining, both individually and in combination with a potent activator of the innate immune system, our toll-like receptor 7 agonist UGN-201. The results of these studies suggest that bladder cancer treated with the combination of TLR7 agonist and an anti-CTLA-4 antibody in our RTGel produces improved survival compared to treatment with other checkpoint inhibitors, either alone or in combination with UGN-201. This is important for a variety of reasons. First, we've shown that intravesical delivery of combination immunotherapy is potentially synergistic. And second, because CTLA-4, long considered a good target for overcoming immune suppression produced by cancer cells, is toxic when administered systemically. Local delivery using our platform may permit us to leverage the power of a highly potent antibody while avoiding the toxicity associated with intravenous administration. This is critical because anti-CTLA-4 stimulates cytotoxic T-cells while inhibiting suppressive T regulatory cells, making it a potentially more comprehensively acting immunomodulator than antibodies to PD-1 or PD-L1. Independent of our own laboratory work, there is good evidence from clinical trials and other disease states to support the use of checkpoint inhibitors in combination with other immunomodulators, chemotherapies, gene therapy and in making immune stimulators. We view our in-licensed anti-CTLA-4 antibody, zalifrelimab, which we refer to as UGN-301, as the cornerstone of a program we are pursuing in collaboration with MD Anderson Cancer Center along with Jim Allison and his colleagues. Non-human primate toxicity studies are underway to facilitate the initiation of a multi-arm Phase I study of UGN-301 in combination with other agents, and is planned to begin in 2022. We believe this approach leverages our unique platform for drug delivery and provides an opportunity to evaluate a way by of immunomodulatory drug combinations, including agents such as interleukins, STING agonists, TIGIT blockers and chemotherapeutics. I'm now joined by 2 surgeon scientists who have a significant interest in the development of potential new treatments for patients with bladder cancer. I'm pleased to welcome Dr. Karim Chamie, Associate Professor in the Department of Urology at UCLA Medical Center; and Dr. Josh Meeks, Associate Professor of Urology, Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine, who will join me to discuss more about the unmet needs of patients with high-grade NMIBC and the potential for locally applied combination therapy. Dr. Meeks and Dr. Chamie, welcome and thank you for taking time to speak to us today. Before we get started, I'm required to note again that the panelists are representing their own views and not necessarily the views of their employer or affiliated institutions. Additionally, both are consultants of UroGen and have been compensated for their participation in today's event. So without further ado, let's begin with our questions. Dr. Chamie, let me start with you. High-grade non-muscle invasive bladder cancer is a different disease than UroGen has focused on in its first development programs. Tell me about the current management of patients with high-grade, non-muscle invasive bladder cancer, what do you think the unmet needs are for patients with this form of bladder cancer and perhaps what the challenges are the doctor is facing caring for these individuals.

Thank you, Dr. Schoenberg. So patients with high-grade, non-muscle invasive bladder cancer are kind of stratified into intermediate and high risk. And that's primarily based on the European Association of Urologists, which has come up with a set of guidelines based on tumor size, tumor location as well as the American Urological Association. So the combination of both guidelines has set forth some recommendations as far as how we treat these patients. For patients who have intermediate risk disease, namely patients with high-grade TA, smaller tumors, the guidelines recommend that these patients be treated with intravesical chemotherapy or BCG. For patients who are high-risk disease, meaning they have CIS, carcinoma in situ or high-grade T1, the guidelines would recommend that these patients get BCG. Some of the challenges that we encounter in this population, one, currently, there's a BCG shortage. There's one major manufacturer of BCG globally and currently we're splitting doses of BCG for patients even those -- even some of those patients with high-risk disease. And we know that patients who have high-risk disease benefit from full dose and long-term BCGs. The other components are that there was a study that UroGen helped support that looked at the natural history of patients with bladder cancer. And obviously, these patients have multiple recurrences and there are a number of long-term sequelae, namely, lower urinary tract symptoms that don't go away immediately after surgery. And those are some of the unmet needs that patients with high-grade bladder cancer currently experience.

Thank you, Dr. Chamie. Very helpful. And I think a nice segue to the next question, which I'm going to direct to back to Dr. Meeks. Dr. Meeks, immunotherapy in the form of BCG has been a mainstay of treatment for high-grade, non-muscle invasive bladder cancer for decades, but it's in short supply now. The recent approval of an intravenous checkpoint inhibitor has been heralded as a real breakthrough for the BCG-unresponsive population [ and suppose ] by extension for patients who have high-grade disease, particularly when patients have had multiple courses of BCG and are considering the possibility of having to confront bladder removal as an alternative therapeutic strategy. What's your view of the availability now of intravenous checkpoint inhibitor therapy for this population, a little bit about the toxicity perhaps of that approach? And could you comment on whether or not an intravesically delivered checkpoint inhibitor would provide a promising or interesting alternative?

Thanks Dr. Schoenberg. I think that the checkpoint immunotherapies have really revolutionized how we treat cancer in general. The challenge, though, is all the data has really been built on the metastatic setting and ably worked that back to the non-muscle invasive disease setting. And the disease is somewhat different. So we've looked at how effective those drugs are. And the good news is that there is a population of patients that respond and seem to have a durable response. So it's great for them. I'd say that the challenge is that many patients don't achieve a response, so that most of the data is based on a 3-month evaluation where people have -- should have cleared their cytology and have had no evidence of carcinoma in situ in the bladder. And so the real challenge is that many people still don't respond to those drugs and so we don't have a whole lot to offer them. Even though we think that a lot of those immune regulation mechanisms likely play a role in early-stage bladder cancer, but simply giving IV therapy to manage carcinoma in situ probably may not be -- we know may not be the best way to treat this. So I think there's still, on balance, more interest and more hope and a lot of science and a lot of biology to be explored. Certainly for those who respond, checkpoint therapies really helps a lot of patients out. But I think there's a lot more that can go forward. And really, some of that may be on the delivery. Again, when you think about a drug delivered through the IV and it has to go through the blood, get to the urothelium, we just don't know about that delivery mechanism. And I think that's where our hope is that we'll be able to put a drug in directly to the bladder to affect the urothelium, and specifically that carcinoma in situ which sits on top of the urothelium, in order to better deliver those immune-regulated agents.

Wonderful. And you anticipated my next question, which I'm going to direct to you. Given the fact that UroGen is really interested in pioneering local deliveries of combinatorial immunomodulators, can you talk a little bit about, based on your own personal experience and our scientific background, what mechanism might be at play when you apply immunomodulators directly to the interior of the bladder?

So I think this is a huge area of scientific and clinical interest, right? We know that there are definitely immune cells there. Anyone that's looked in the bladder sees that there's a copious amount of immune cells that are present when you treat a patient with bladder cancer. And really, again, a lot of the drugs running through the IV, we don't really know how much that is diffusing in some of the blood supply which is mostly going to be in the lamina propria into the urothelium and the cells that are there. So I think that the hope would be that coming from the urothelium inward, where there's still many of those mean cells. And again, where carcinoma in situ sits right on top of the epithelium, that there may be some immune regulation that occurs to either be pro-inflammatory or turn off some of those exhaustion mechanisms so that the T-cells that are there, the immune cells that are there, can actually be reawakened and actually do the job that we're hoping that they need to do.

Just a particular relevance to the BCG refractory population, do you think?

I do. I get a -- we're sort of finding more out about that patient population. We've all put everyone in this box of BCG unresponsive because of the see the certain number of doses. Again, I think there's a lot we need to figure out about why people don't respond to BCG. But certainly, we think that there's a lot of points to develop in a new response and the system has set up with check and balances. So the reason we've evolved and the way the system works, when you turn on a pro-inflammatory response, it's quickly turning that off. Otherwise, you would have autoimmunity. So there's a lot of checks and balances that need to be regulated. And one of the theories that we have is that there are patients who were able to get an immune response but then the body kind of shuts that down. And again, to avoid toxicity or too much immunity. But in patients with bladder cancer, you actually still get a benefit from that. So that's kind of where we think that window of trying to reawake or reactivate the immune cells in a more localized fashion can make a lot of sense.

Thank you. Dr. Chamie, UroGen has spent a lot of time perfecting its delivery platform, and I'm curious to what other immunomodulators are interesting drugs you think the platform could deliver in the context of intravesical therapy. Wonder if you would comment on that.

So I mean we -- there are multiple opportunities. I mean urologists are adept at instilling agents into the bladder and have seen remarkable outcomes. So you have chemotherapy. So obviously with UGN-101, you've got mitomycin; and 102, you have mitomycin but potentially they're other chemotherapeutics agent, gemcitabine and docetaxel. In addition, there are immune modulations, such as the 301 or 302 program involving CTLA-4, as well as the TLR7/8 agonism. So that's where I see potential immunomodulation between TLR7/8 agonism combined with CTLA-4, or potentially a checkpoint inhibitor like an anti-PD-1 or PD-L1.

Great. Dr. Meeks, you know that UroGen has been focusing particular attention on developing locally applied anti-CTLA-4 antibody in the treatment of high-grade, non-muscle invasive disease. What else might you combine specifically with that checkpoint inhibitor?

Yes. So if you think about how that one is going to work, we think there's a central role, right? But also locally, there's a lot of immune cells that express the CTLA-4 receptor. So for example, Tregs and other like regulatory growth cells. But additionally, if you think about work to bring in an immune response, pro-stimulatory things, because again, those are shutting off the exhaustion. So then you probably need to combine that with something that's going to be very pro-inflammatory. So anything that's going to bring immune cells and take a quiet or a cold tumor and bring in things. Again, we use BCG quite a lot, right, because we know that that's very pro-inflammatory. But as Dr. Chamie mentioned, there's a number of molecules that can stimulate an immune responses. But coupling a pro-inflammatory with something to turn off the exhaustion seems like you're getting rid of the brake and you're really stepping on the gas as well.

Let me ask both of you, and I'll turn it back to Dr. Chamie first and then come back to you, Dr. Meeks. So you spend -- both of you spent a lot of time thinking about this area and you both do research, both in clinical trials and also in the laboratory on this area of bladder cancer care. What else has caught your eye recently, other agents or approaches that you think or were thinking about in the context of developing UroGen's platform and pipeline?

Well, outside of UroGen's platform and pipeline, I mean, there are -- there is a clinical trial that I'm the principal investigator of, which is the IL-15 superagonist N-803 in combination with BCG, and that's intriguing because it's going down a completely different pathway. I mean most people think that maybe 803 plays a role in turning down Tregs, I think its primary role is probably through natural killer cells. And I think the future of integrating the innate immune system, at least in the tumor microenvironment or in the bladder, would be the next frontier as far as local delivery of treatments.

Dr. Meeks, how about you?

Yes, I would second that. That's a very exciting trial. I think there's a lot of hope and a lot of interest in that. I would say that my interest kind of move a little more towards the precision-based approaches in the sense of I think there's probably 2 to 3 different diseases that are kind of going on here. And so I'm trying to figure out and pair tumor to therapy makes a lot of sense to me. Because I don't -- I just think at this point after patients have been treated with first-line therapy and were sort of already at a second stage, having a better sense of why they didn't respond makes sense. So I like the thought of sort of investing in the translational work to [ feed ] for on the really novel therapeutics.

Well, wonderful, thank you both very much for your thoughts and your observations about this very interesting and data in the field. We really appreciate your time, and thank you for joining us this afternoon. [Presentation]

Hello, everyone, and the other Q&A panelists. So first I wanted to say thank you for joining us this morning, this afternoon and this evening, wherever you are as we spotlight our new -- our company and the progress that we're making. I would say the last few years has been very, very challenging. Very -- oops, sorry. Are we okay? Can everybody hear me okay? Okay. Good, thanks. And so let me, again, take the opportunity to thank you. We're excited about highlighting where we are in our journey. As you heard from the video presentations and from the patients as well as from the panelists, we're excited about the future of UroGen. We really spent a lot of time making sure that we remain true to our values around people and they connected and one of the areas that we've really spent out of time on, as you heard, was in working with the FDA to educate them on the strategy because low-grade non-muscle invasive bladder cancer from a medicine standpoint is not something they were very familiar with, and I want to take the opportunity to thank my team at UroGen and some of our scientists have also taken the opportunity to spend time with us as we worked with the FDA. And -- but importantly, beyond Jelmyto and UGN-102 to really highlight where we're going and where our future is at UroGen. So, as we talked many times, the foundation of our company with our T-cell we really want to be the premier company in urothelial cancer. We want to move into other specialty cancers where we believe that local delivery can be a new treatment paradigm to those areas. And then lastly, obviously, where in other therapeutic areas are important as well as other companies as we move the urothelial platform. So with that, I'm just going to stop now and open it up for Q&A. So Lee?

Thanks, Liz, we'll pause for just a second to compile Q&A roster. And our first question is coming from Boris Peaker at Cowen.

So I guess the first question is, I guess, as far as the unusual to start a Phase III study and then stop it in the middle and change the development plan. Can you comment on what exactly happened to drive this change?

So, I'm going to actually turn it over to Lee, who is our Chief Development Officer, to talk to you about it. We have been working and talking to the FDA long before actually joined emerging. When we launched the UGN-102 program and one of the things that the FDA has been looking [indiscernible] what they consider to be standard of care. Elyse can comment more on this as well. And they're a believer that there is really is the standard of care, and there's no need for anything out there. I mean, that would be initially their perspective. And we've really worked hard to help them to understand not only some of the detriments of repeated TURBT, but I understand this patient population. And so with that, if you're right, the sense of what it took us time and we wanted to start the study and bring that in as quickly as possible. And -- but we, again, continue to work with the FDA to make them understand that forcing a company by surgeon or any company to do a head-to-head cancer surgery. Frankly, it never happens before. They don't say they at least hurricane is a nice job beginning of other examples of where other drugs have been approved with single-arm study because they weren't forced to do any in surgery. And so we just felt like it was a more streamlined approach. But Elyse, do you want to just comment on this and sort of our journey with the FDA and why we did start our behalf of our study.

Mark, if you want to add anything at this point. But I think where we netted out with that a more streamlined approach to our Phase III study, a higher probability of success of that study, more knowing and understanding the timing of that study were all the reasons we felt like it was still the prudent thing to do and be able to execute in. Mark, I don't know if you want to add any comments on that?

No, is, I think you hit one of the most important points, which is that it would be exceptional to compare the therapy we're advancing with a surgical compare that we were not able to find a in that it was a viable design. And it took a long time talking with the FDA about that. Thankfully, they've come around.

So the FDA especially agreed as on clarifies new study design for the total trial?

Yes. We were not doing -- would not have made the change, Boris, to your point, had we not gotten an agreement with the FDA, that this could be the basis for a number.

Our next question is coming from the Leland Gershell, Oppenheimer.

On that point, Mark, just a couple of questions from me. It does sound a little bit similar to the OPTIMA II study. Are there any elements that you should call out with respect to the upcoming pivotal that will be different, meaningfully, some OPTIMA II how we should think about that. And I also like to ask our TURBT is well-established in terms of trading for TURBT. Just wondering how the absence of this second arm with surgery will matter down the road when the part is presumably approved on the market versus having had that data set, I guess we'll have some from ATLAS, but perhaps not as robust as you would. So just want some color there.

I'm going to answer the first -- the second question first and then ask Elyse to a comment on the trial. From a practice perspective, what's interesting, I speak personally as someone who's dealing with these patients, but also talking with colleagues, people are looking for this sort of additional option for patients. I certainly am because the patients we're talking about are those are chronically recurring. And so, we know that this population is ill served by our standard of care and they are both, as we discussed previously, clinical and biological reasons to think that the approach that UGN-102 offers is going to really improve how we take care of this population. So, I'm actually personally not concerned about the adoption of the therapy as I think you heard the side in the panel discussion is in the context of clinical practice and caring, there's a lot of appetite for bringing in Asian links into the Asian intern. But let me defer my colleague Elyse to talk to you more specifically about the new trial design and how Asian population that will be the subject of the clinical compares to the Phase II.

Thanks, Mark. And everyone hear me okay. I apologize for earlier. So, there are patient to -- I mean, there's a lot we're leveraging that we launched in OPTIMA II. The patients have the same clinical characteristics that we enrolled in Optima II. The treatment is obviously the same, the assessment of disease at baseline and at the 3-month time point and then follow-up, all of those assessments are the same. I think, certainly, it's a larger study than OPTIMA II study, which was really designed to be a proof-of-concept study. This is an appropriately powered Phase III study, but we really leveraged everything we learned in the study in designing this. I think the biggest difference is that we will follow the patients longer than 9 months after their 3 month assessment, and we'll also follow patients who don't respond through at least our first intervention to understand the history of what happens in that patient population. And the only thing I'll add about ATLAS, I think there will be learnings from ATLAS. Although, we're stopping enrollment early, I think we'll have a robust safety database in both treatment arms. And so, we will have some robust head to head comparative safety data. And obviously, all of these data would be integrated and inputted into our NDA when we do that.

So, can you comment on the pros?

So, we did some exploratory work in our Phase II study using patient-reported outcomes tool assessments. And these are tools that are standardized for the non-muscle invasive bladder cancer population to look at the effective treatment on the quality of life. And we don't really expect you don't want to do to improve some of this quality of life because bladder cancer is largely an asymptomatic disease, we're looking to not bottom. And in the small data set that we had in our Phase II study, we really saw no adverse impact on the quality of life of patients who are treated with UGN-102. I think in this study, we'll have an opportunity to generate a more rigorous and robust database because it's a larger population. And so, I think it's important to really establish what is UGN-102 do or not do in terms of patients who are undergoing compared to what happens in this population when they undergo surgery. And so we'll have an opportunity to collect those data.

Our next question is coming from Matt Kaplan at Ladenburg Thalmann.

Just can you give us a little more color in terms of the new study design in terms of your thoughts on powering for the primary endpoint that you're looking for there at 3 months. And then also with respective durability, what you're looking for in terms of the durability of the effect?

So, the discussions we've had with the agency on this are very similar to the discussions we've had, we had when we were developing Jelmyto. In that it's really important that the data are coning. And it's really the totality of the data. We saw what we saw in Jelmyto. I think it's important to note that the results be gone off to mature were actually quite similar to what we saw in our Jelmyto Phase III program. And so, we obviously do statistics to generate our sample size. But I think here, it's really much more about ensuring that the data that we generate are considered clinically meaningful. And that's clinically meaningful to patients, clinically meaningful to urologists and of course, at the end of the day, clinically meaningful to scientists. I think just sort of comment or add-on that, Matt. I mean, what we the say is that when we powered the study, we took a very conservative approach in the sense of we want to make sure we had enough patients in there where we get a nice robust in the hard and have a nice durability. And so it's not a situation because it's not a comparative study, right. So really, what we do is we looked at what we felt like would be closely meaningful to all of those stakeholders that Elyse mentioned and that's how we powered the study. But 220 patient study and then 65 patient study, in addition to the patients that we'd already rolled in ATLAS, we believe all of that will be a robust data set for us for the base of an approval. And the positions that we've spoken to quite a bit have said that look, if you have any patient and have an opportunity, we talked to physicians where and you heard from Jeff that basically sit at 25% of my patients decided to be going through TURBT. You can be half at patient decisions looking for other treatment options because this isn't working for them. So, we took all that in consideration in developing the number of patients because you can already -- the FDA like all 65 patients isn't enough or how many is in not and the team did a really nice job of developing the analysis and support for 220 patient study.

And just one more follow-up on ATLAS. Did you comment on the number of patients or the data set now that you're suspending enrollment in that study that will be available when you finally stabilize that?

Yes. Not yet, then I think we're going to wait until we -- because there were some cases that were consented and so we'll be closing out those patients. I am happy to say that we did see what you normally see from a -- we like good new bad news because we were having this conversation with the FDA and enrollment was picking up in ATLAS some and so, but we felt like any patient that we can have in ATLAS, any data that we have would be helpful. So we'll provide that information more as we are in the next -- towards the end of the year, maybe when we report out the year, it's how many patients we actually have in hand. And we can actually start to share some data next year on some of the results from the atlases because now that it will be used as from data on the basis for our approval, but more from a context of safety will actually be able to provide some data in 2022.

Thanks all. I'm showing no further questions at this time. Liz, I'll turn it back to you for closing remarks.

Great. Thank you. I just want keep everybody and know we ran over in our event with was longer than we expected, but we really wanted the opportunity to share with you more about our pipeline, UGN-102, but also highlighting 301, how we are making 301 of the cornerstones of the therapy idea and treatment for patients in the ulterior cancers and in other cancer specialty cancers as well. So stay tuned. We look forward to picking up what all of you guys and take care. Bye-bye.