Protara Therapeutics, Inc. (TARA) Earnings Call Transcript & Summary

Hello, and welcome to the Protara Therapeutics SUO Update Call. [Operator Instructions] Also, as a reminder, this conference is being recorded. If you have any objections, please disconnect at this time. With that, I would now like to turn the call over to Justine O’'Malley, Senior Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. Good morning. Thank you all for joining us today for a review of the updated interim results from our ongoing Phase II open-label ADVANCED-2 trial of TARA-002 in patients with non-muscle invasive bladder cancer. Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. These statements represent our views as of today only and should not be relied upon as representing our views as of any subsequent date. Actual results may differ from our forward-looking statements due to various factors, including those described in the Risk Factors section of our most recent annual report and subsequently filed quarterly reports that are on file with the SEC. Except as required by law, we disclaim any obligation to update these statements, even if our views change. I will now turn the call over to Jesse Shefferman, Co-Founder, Director and Chief Executive Officer.

Thank you, Justine, and thank you all for joining us this morning. Following last week's exciting release of data in our lymphatic malformations program, we are equally excited today to present another positive data readout for TARA-002. 002 has a potential best-in-class product profile in NMIBC with compelling response rates, encouraging durability and adoption-driving safety and tolerability profile. These, along with its off-the-shelf availability and simple administration, position TARA002 at the intersection of factors that are priorities for NMIBC patients and urologists. Today, we will be presenting updated positive results from the BCG-Naive patients in our ADVANCED-2 trial. The 50% complete response rate at 12 months underscores the strength and durability of the response driven by 002, which we believe has strong potential in the BCG-Naive patient population. In addition, we continue to enroll BCG-Unresponsive patients in the registrational cohort of ADVANCED-2 and anticipate full enrollment of this cohort in the second half of 2026. Further, we remain on track to report interim results in the first quarter of 2026 from at least 25 patients, who are at a minimum 6 months evaluable in the BCG-Unresponsive cohort. Today, I'm joined by Dr. Leo Nicacio, our Chief Medical Officer, who will walk us through the updated data momentarily; as well as Dr. Jackie Zummo, Co-Founder and Chief Scientific Officer of Protara, who will provide an overview of next steps for the program, including recent FDA feedback on the BCG-Naive path. Finally, we are privileged to be joined by Dr. Neal Shore, Medical Director at the Carolina Urologic Research Center. Dr. Shore will walk you through the current NMIBC treatment landscape, including key areas of unmet need and offering his thoughts on where 002 may fit in. At the conclusion of our prepared comments, we will open the call for Q&A and are joined for that by our Chief Financial Officer, Pat Fabbio; and our Chief Commercial Officer, Bill Conkling. For those of you who may be new to the Protara story, we are a clinical-stage company developing transformative therapies grounded in strong biologic rationale for the treatment of cancer and rare diseases. Our lead asset is TARA-002, a genetically distinct strain of strep pyogenes that drives an immunologic attack of mutated cells. In addition to assessing 002 in NMIBC, as I said earlier, we are also interrogating 002 in lymphatic malformations, which are rare congenital malformations of lymphatic vessels, typically diagnosed in childhood. And finally, our pipeline includes IV choline chloride, an investigational phospholipid substrate replacement for patients dependent on parenteral support, for which we expect to commence a registrational study by year-end. We are excited for the potential that all of our programs hold to make a meaningful difference in the lives of patients. Today's focus will be on the BTG-Naive cohort of patients in our ADVANCED-2 trial. Before I turn the call over to Leo, I would like to take a moment to talk about 002's mechanism of action. TARA-002 is a unique TLR2/NOD2 agonist and an immunopotentiator that engages both the innate and adaptive immune pathways within the bladder wall to drive M1 macrophage polarization, cytokine release and recruitment of NK and cytotoxic T cells. The result is a potent localized antitumor immune cascade that directly targets abnormal urothelial and cystic cells. In essence, 002 puts the immune system in targeted attack mode, creating a focused local response without excessive inflammation. 002 is fully inactivated, bringing a new and differentiated immunologic mechanism to NMIBC beyond BCG and other targeted approved and investigational treatment options. 002 was developed from the same master cell bank as OK-432, a broad immunopotentiator marketed as [ disecibinal ] in Japan by Chugai Pharmaceuticals, where it is approved in several oncologic indications as well as LMs and benefits from a 65,000 patient safety database. Protara has successfully shown managed manufacturing comparability between 002 and OK-432. And as many of you are aware, across the various mechanisms and modalities employed to treat NMIBC, 002 is most similar to BCG, which is the standard of care for NMIBC. Both are bacterial immune potentiators that drive a Th1 pro-inflammatory response. Like BCG, 002 triggers an immune cascade but with a distinct cytokine signature. Compared to BCG, 002 has higher upregulation of key pro-inflammatory cytokines and chemokines, including TNF alpha and interferon gamma. Notably, 002 downregulates IL-8. This is important because IL-8 is known to be associated with tumor recurrence in NMIBC. And of course, recurrence is the primary focus of therapeutic intervention in NMIBC. As I mentioned, 002 is completely inactivated while BCG is attenuated. This means 002 has a more favorable safety profile compared to BCG and it is easier to administer as there are no extra precautions to manage a live bacteria, no need for post-administration burden on the patients, such as needing to use a separate bathroom or perform urine bleaching to not spread infection at home. These important attributes position 002 to be a potentially meaningful alternative treatment option to BCG in the frontline setting. With that, I would like to turn the call over to Leo to walk us through the data.

Thank you, Jesse. It's a pleasure to have the opportunity to review this exciting update. As a reminder, ADVANCED-2 is an ongoing Phase II open-label clinical trial assessing Intravesical TARA-002 in NMIBC patients with carcinoma [ in cyto ] with or without papillary disease, who are either BCG-Unresponsive or BCG-Naive. The BCG-Unresponsive cohort has been designed to be registrational, in alignment with the FDA's updated 2024 BCG-Unresponsive NMIBC guidance. And the BCG-Naive cohort, which we'll be discussing today, is a proof-of-concept study. Patients in the trial received an induction course with or without reinduction course of 6 weekly intravesical installations of TARA-002, followed by a maintenance course of 3 weekly installations every 3 months. Patients are eligible for reinduction if they have residual CIS and/or recurrence of high-grade Ta at 12 weeks. They are not eligible for reinduction if they experience disease progression or treatment failure. The primary endpoint of this trial is CR at any time, with durability of response as a key secondary endpoint. The data set being presented at SCU meeting includes 31 BCG-Naive patients, who received at least 1 dose of TARA-002. Of these patients, 29 completed at least 1 response assessment and were assessed for CR at any time. 26 were evaluable for efficacy at 6 months, and 14 were evaluable at 12 months. Two patients discontinued the study prior to reaching the 3-month evaluation time point as of the November 7, 2025 data cutoff. The complete response rate at any time was 72% with a 6-month CR rate of 69% and a 12-month CR rate of 50%. Reinduction therapy successfully converted most initial nonresponders to responders at 6 months, resulting in a high conversion rate and durable responses. 80% of the reinduced patients converted to CR at 6 months, and 100% of those responders maintained the CR at 12 months. We are pleased with the efficacy results demonstrated by TARA-002 and are highly encouraged by the strong durability at 12 months. Moving on to safety, TARA-002 continues to demonstrate a favorable safety and tolerability profile in BCG-Naive patients. Consistent with previously reported results, the majority of the treatment-related adverse events were grade 1 and transient, with no grade 3 or higher treatment-related adverse events, as assessed by the study investigators. And no patients discontinued therapy due to treatment-related AEs. The most commonly occurring treatment-related AEs in this cohort were [ diarrhea ], fatigue and hematuria; consistent with what we would expect for a bacterial immune potentiator. Importantly, there were no treatment-related serious adverse events and the overall profile supports continued development in both frontline and previously treated populations. When we put all the pieces together, TARA-002 profile sits at the intersection of what both patients and urologists prioritize, safety, efficacy and simplicity. 002 delivers robust single-agent activity with competitive complete response rates and encouraging durability. It does so with a clean safety profile, no related serious events, no discontinuations and only mild self-limited local reactions. And it is administered through a simple office-based intravesical installation, no viral handling, no special preparation, making it easy to integrate into existing workflows. A compelling efficacy and tolerability profile, combined with practical delivery positions TARA-002 as a best-in-class next-generation investigational intravesical therapy with the potential to meaningfully advance care in NMIBC. With that, I will now turn the call over to Dr. Shore.

Well, thanks very much, Leo, and a pleasure to be here today with everybody, and great data that's being presented at SUO. Just really briefly, as Jesse mentioned at the beginning, I'm the Medical Director for START Cancer Research, Carolina Urologic Research Center, and I head up the GU oncology consortium for START cancer. I've had the privilege of being involved in bladder cancer research, NMIBC, MIBC, metastatic; for much of my career, was a founding member of the bladder cancer think tank and 10-year Board member of [ Beacon ] and also started the bladder cancer organ site for the SUO clinical trials consortium. I think, I guess to just keep it to NMIBC today for the purposes of our content, we always are looking at this BCG-Unresponsive as a predicate for thinking about potentially even the BCG-Naive population. The unresponsive space, as many of you know now who are looking at it, is a quite complicated space and there are more and more folks are looking at the naive. I actually think Slide 13, which Leo just presented that Venn diagram, beautifully positions TARA-002 for incredible success. And the proof of concept and the naive is rather impressive, given the data that's getting presented from ADVANCED-2 today and going forward. At the end of the day, there has to be efficacy, it has to be reasonable, there has to be the other important considerations, not only the safety and tolerability for the patients, which it's impressive, the thousands and thousands of patients who've been exposed to 002 in the U.S. and primarily in Japan, but I think more importantly, at least from my perspective, is we see this plethora of alternative therapies now entering into the unresponsive, but in the BCG-Naive where there's clearly challenges in production of BCG, which everyone should be familiar with, particularly in the U.S., inconsistencies of the strain. Alternatives such as 002 are particularly compelling to me, this is really -- this is highly non-incremental. This, to me, would be an enormous improvement for community-based, especially where challenges exist with implementation of some of the more complicated therapies. Not at my sight, I'm kind of a research wonk, I like all that. We have facility, but that's just not the case in the vast majority of community centers, frankly, not only in the U.S. but outside the U.S. So I've had an incredibly positive experience with 002, both in the BCG-Unresponsive and now in the Naive. I'm really excited for ongoing trials to further explore that. I think it's a particularly fascinating area within the the naive because that's a huge unmet potential, given the BCG shortages, given the intolerability for some patients with BCG, given the manufacturing issues. So I'm very enthusiastic for it. It's a crowded busy space, but I think that the 002 really kind of sets itself apart with a really robust safety profile, a simplicity. And simplicity is not to denigrate that, but it is very important in terms of throughput in practice. There is a well-recognized person power shortage of clinicians, of the team of medical assistance and nurses and LPNs. And having, to me, something that doesn't require so much of the complexity and the biohazard concerns that were already articulated, really kind of potentially sets 002 quite apart from the field. So let me stop with that for purposes of time, and thank you for allowing me to address you.

Thank you, Dr. Shore. Although BCG is effective when it's available and administered as intended, we know that up to 40% of frontline high-risk NMIBC patients do not receive it. The FDA recognizes there is limited approved treatment options for these patients. In addition, surveys have demonstrated that urologists consider development of non-BCG-based alternative therapies as a high priority for BCG-Naive higher patients. With TARA-002s compelling results, we've worked with the FDA on an agreed-upon registrational path forward for TARA-002 in the BCG-Naive NMIBC patient population. The FDA has provided written feedback aligning on a registrational trial for a controlled trial in BCG-Naive patients. Based on TARA-002 mechanism of action and existing data to date, the agency has agreed that BCG is not required for the comparator and that intravesical chemotherapy is an acceptable comparator in our BCG-Naive population. The agreed-upon trial endpoints include primary endpoint of landmark CRE at 6 months and a key secondary of duration of response. Given that BCG is not required in the study comparator, our trial will be fewer than 500 patients. With this feedback, we are able to move forward with this registrational study in BCG-Naive patients. We have engaged the FDA on how best to study 002's efficacy and safety in the BCG-exposed patient population. There remains a significant unmet need in the BCG-exposed population, for which no FDA-approved treatments are available and who have limited options to access the investigational treatment through our clinical trials. We look forward to providing additional information on the study population based on our interactions with the FDA. With that, I'll now turn the call back over to Jesse.

Thank you, Jackie. We are very excited by these positive data. They further build upon 002's potential as a meaningful treatment option for high-grade NMIBC. We believe there is significant need for new treatment options in the BCG-Naive setting and we are encouraged by the consistent and durable CR rates demonstrated by 002 in this patient population. We're enthusiastic about the potential for a randomized controlled trial to provide a level of evidence and differentiation that we believe will drive earlier-line use of 002 in high-grade, high-risk NMIBC. At Protara, we are truly focused on the patients we hope to serve. So while today's update represents another exciting development for our company, more importantly, it represents a potentially groundbreaking development for the many patients and physicians, who require an alternative to BTG. 002's target product profile fits at the intersection that NMIBC patients and their providers prioritize. With its demonstrated efficacy and safety profile, it's observed durability and tolerability, it's ease of use as well; we believe 002 has the potential to be the seed treatment of choice among urologists treating NMIBC. I would now like to open the call up for Q&A. And out of respect for Dr. Shore's time, we ask that you focus your questions on the NMIBC program at Protara. Operator?

[Operator Instructions] Your first question will come from Stacy Ku with TD Cowen.

Congratulations on the really competitive results in the bio-naive patient population and the really encouraging FDA feedback. I know the team has worked on this for a really long time. So just a wonderful update. So we have a couple of questions for Dr. Shore first. So you alluded to some of the BCG shortage, and [ Merck ] is hopefully going to address some of this. But just help us understand, if there is unlimited supply as we think about induction and maintenance, how much more BCG would you have wanted to use? And of course, if TARA-002 was approved in first line, how would you differentiate 002 in BCG? So that's the first question. And then the second question is in the real world, maybe talk about the efficacy of BCG that you're seeing. And maybe help us understand when it comes to the CIS population and the papillary patients, how do we make -- what do you make of BCG performance and how do we compare that to the efficacy we see for TARA-002? So kind of the real-world BCG versus what we're seeing today, maybe talk in a little bit more detail than what you said in the prepared remarks. And then last, maybe help us understand the level of, I would say, SUO, the level of, I would say, community feedback or KOL feedback in terms of urologists and their level of enthusiasm for having other options in the first-line setting. And I have some follow-ups for the company.

Sure. Happy to, Stacy. Thanks. So yes, my remarks were spontaneous, but I will tell you that, yes, a lot to unpack in your question. Let me try to hope hit all your questions. So we used to have 2 -- Sanofi dropped out, they closed down their plant. There's only one plant in the United States, the Merck plant, and it's being redesigned and hopefully will come online and be more efficient. The BCG shortage in the [indiscernible] strain in the U.S. has been -- it comes in cycles. As you're probably aware, it's unpredictable, it's variable. I, for a long time at my site, we didn't have an issue. Currently, we're having an enormous issue. About 50 patients right now are waiting, can't get product. And that's kind of the experience that I've seen from colleagues all over the United States. It's somewhat unpredictable, based upon historic ordering patterns. So we'll have to wait and see regarding that. In terms of -- it is the gold standard, right? We use that word for lack of something better to look at. There are some studies that are looking to maybe replace that, the upcoming BRIDGE trial with combination chemotherapy. The problem I see with that Gem/Doce, although it can be effective, is it's arduous to administer, it's time consuming, the economic modeling for it is poor based upon U.S. health care economic dynamics. That said, it has a sort of significant appeal within academic centers, I understand that. But honestly, I don't see it with rapid adoption in the community. We give it, but I don't really see that from a long-term practical aspect. If 002 were to successfully complete this trial that Jesse very clearly articulated, not only in the naive, but also in the exposed; that is an enormous population. BCG, albeit an excellent product, an immunopotentiator, attenuated as opposed to completely inactivated, which is another theoretical advantage to the 002; nonetheless, has intolerability issues and the arcane nomenclature that we're moving away from. Intolerable. We don't tend to use that, but there was a reason why that was part of the verbiage. We just don't see that in 002. So in terms of community urology, in terms of patient user friendliness, I think it's -- it can't be underestimated how important that is. So -- but yes, when given correctly in trial, BCG can be remarkably effective. Now maybe just transition a minute to the exposed population. That is an enormous population of patients who had less than adequate 6 plus 6 or 5 plus 2 and maintenance therapies. And that's a really incredibly interesting population that frankly, Protara and other companies are looking at. And I think it's really smart of Protara to look at that in addition to the purely BCG-Naive population.

Okay. So would you characterize then, I guess, the limitation of BCG as 1x, 2x, 3x, 4x, how many times, I would say, is -- obviously, you're saying in cycles. But when it's taking the totality of the cycles, what -- how much more BCG would you have wanted to use if you had unlimited supply, to ask it differently?

I guess maybe to ask -- to answer it a little differently, if 002 were approved and I had unlimited BCG and it was not superior but just noninferior, so equivalent, given the safety profile, given the biohazard concerns we have with BCG, the bleaching, not just at home for the patients, but if they have incontinence and episodes; you have to shut down facility. You don't have that issue with 002. So I would say, to answer that if with noninferiority, I wouldn't see a reason to use BCG.

I see. Wow, that's very helpful. Okay. And then maybe to the company, as it relates to the type of trial design that you would need versus chemotherapy, are you able -- very early as I understand, are you able to talk about maybe some of the potential powering assumptions? How -- given your experience with this study over enrollment, how quickly could you get to a potential study initiation and timing for results? I know very early days, but kind of curious if you guys could elaborate.

Yes. Thanks, Stacy. Great to hear from you. You raised a good point, it is early days. We have a first mover advantage here, given this -- where we are with the FDA. We're ready to go, is what I would say. We have answers to a lot of the questions that you raised. I think we tried to address them as directly as we can while still kind of taking into account the benefit of Protara being in a position in NMIBC with a first-mover advantage. So what I can say is we believe that the numbers that we talked about, a number of fewer than 500 patients, is pretty set in stone for the BCG-Naive patients, who would qualify for this study. We are still in active dialogue with FDA, as Dr. Shore noted, about the very large exposed population and whether that becomes a part of this study or its own study, and that will depend on the degree to which we need to be looking at subgroup analyses. But the opportunity presented in just the BCG-Naive, not including exposed, is quite large, it's well powered at fewer than 500 patients. And to give a sense, we have been actively enrolling our unresponsive study and are really happy with where we are on that front. But nevertheless, we know from our own experience that we enroll about 5 naive patients for every 1 unresponsive patient in the 2 cohorts of ADVANCED-2. Another interesting point to raise, maybe germane to your conversation with Dr. Shore, is of the 31 patients that we dosed in Cohort A of ADVANCED-2, so BCG-Naive patients; approximately 90% of those patients were dosed at sites that had BCG. So a, we think that speaks to the value of 002 sort of in a BCG agnostic environment. And it also speaks, I think, to the pace at which we believe we could enroll a study with the broad parameters that I've just sort of described for you.

Our next question will come from Li Wang Watsek with Cantor.

Congrats on the data. I guess, first for Dr. Shore, just following up on your comments earlier about Gem/Doce, just curious if you can maybe elaborate a little bit more on 002's profile so far versus some of the options that are currently you're using for BCG-Naive patients, but for various reasons, they can't get access to BCG or don't want to. That's number one. And number two is, can you just talk a little bit about what proportion of patients in your practice that will be eligible for 002? And just given the profile you've seen so far, how can this be potentially adopted in the context of not just chemotherapy, but the other competitors in the space?

Yes. Thank you. So when we have a BCG shortage, we've not had success in split vial dosing. There's a lot of complexity to that from using appropriate [ J ] coding, getting patients in, splitting vials, reimbursement concerns about not doing it appropriately. I think some sites have, but it's a bit messy to try and figure that out just from scheduling and proper coding. When we have a BCG shortage, which is pretty well described in virtually every center in the United States now, academic and community; you run -- you have the technically non-approved but utilized intravesical chemotherapies. At least in the U.S., we have gemcitabine, docetaxel in combination with gemcitabine, almost never given by itself and then mitomycin. Mitomycin utilization, I think, has decreased significantly. We have all three of those, largely due to its complication concerns. And so we've done some market analysis on this. And the most commonly used treatment outside of BCG in the naive is just gemcitabine. Gem/Doce, much more attractive and utilized in academic centers, markedly less so in community because of the reasons I talked about earlier, the throughput, the reimbursement methodology and some of the safety concerns. So I do think that a product such as 002, I thought it was compelling what Jesse just said that he's absolutely right. in the BCG-Naive, these trials enroll very quickly. And one can see that in other products that have been out there, much, much faster than in the Unresponsive because of the requirement for the workshop, which I was happy to be part of with FDA, the 5 plus 2 or the 6 plus 6 or reduction. So it's much more challenging in addition to the time typically having had the treatment, the BCG use within a 12-month period. So that exposed population is enormous, and the BCG-Naive to enroll this particular trial would go very, very quickly. Again, because of the safety profile of 002, which I think is rather robust and very clear, the chemokine cytokine profile does lend itself to a very understandable mechanism of action that I think all uro-oncologists would recognize, both from a lot of really good preclinical work that the company has done. So Yes, we have access to all of the intravesical chemo. Different states -- different parts of the country have nursing issues regarding the use of hoods and biohazard limitations. None of that is applicable to the use of 002.

Okay. Great. Another question on -- yes, sorry. Yes. So I have another follow-up on the BCG-Naive trial design. I wonder if you guys can confirm what the chemotherapy as a control arm would be? Is that going to be [indiscernible]? Or is it going to be physician's choice? And in terms of the gating step for the trial, it sounds like you guys are still figuring out what patient population might be, is that sort of the main piece that you need to align with FDA? Or are there other variables that you need to get clarity on?

Thanks, Li. I'm going to ask Leo to handle the first part of your question, which is what are we thinking about? What have we discussed with FDA on comparator? And then I'll talk more broadly about where we sit in terms of our ability to stand up the study.

Leo Nicacio. So our intention is to have a very pragmatic trial. For the control arm, our intent is to use intravesical chemotherapy for physician's choice, limited to the most commonly used regimen in this setting. The intent is to reflect the real-world practice, and we are still finalizing the specifics with investigators and regulators.

I think it's safely to basically piggyback off of Neal's comments, the way that he described the utilization of Gem, Gem plus Doce, docetaxel mono and mitomycin, with the vast majority of those being Gem; that's how you probably ought to think about a comparator here. In terms of standing up the study, what I can tell you is that we have already quietly been in touch with all of our current sites, multiple potential sites. They are aware that this is a study that we are strongly considering moving forward with. We are good to go, is what I would say. And following this call, you would expect that we would be moving quickly to kind of formalize what we would call ADVANCED-3 as a study going forward.

Our next question will come from Rohan Mathur with Oppenheimer.

This is Rohan on for [ Le Gershell ]. Congrats on the update. I just wanted to ask on the BCG-Naive setting. Given 002 similarity to BCG from an administration perspective, how are you thinking about its positioning next to BCG in the eyes of urologists as a potentially first-line choice?

Yes. Thanks, Rohan. Look, I'll take this and if Neal has any sort of real-world thoughts. But I think the reality is that the similarity in administration is, in our view, a real plus as we think about this product profile that we've described as sort of the perfect balance of the elements that physicians treating urologists and patients want to see in an NMIBC product, right? And so of the three different domains, efficacy, I think we're showing that, that's a real strength for us. Safety, absolutely, we believe we've got best-in-class safety. But the ease of use and tolerability, right, I think you probably could tease out from Neal's comments, these urologic practices are busy. They have a lot of patient throughput coming through, always facing staffing shortages. And so anything that you can do to sort of minimize the sort of pause of a day's cases is beneficial. And so given that this really looks like the Lamm protocol that is the protocol that defines the usage of BCG, that is another point of favorability for us. You don't have to really retrain an entire staff, who have to take time out of their day to learn how do you administer this new thing? And how many steps are there? Oh, it's just a simple reconstitution and saline, fully catheter, 15 minutes and the patients back home with their family. So to us, it's just one piece of a mosaic of factors that we're now demonstrating with 002 that makes us feel like we've got a potential best-in-class product profile.

Got it. And if I could just ask a follow-up on the efficacy. As you interpret the efficacy in these patients who haven't really seen any immune priming from BCG, are you viewing those responses as more meaningful? And do you think that prior immunologic activation could actually make naive tumors more responsive to an immune stimulant like 002?

Yes. So we -- there's a lot that we could dive into with that question, but let me just sort of tackle, I think the most important piece, which is first, the inclusion criteria for BCG-Naive patients in this ADVANCED-2 Cohort A did not say the patient could have required 0 prior BCG exposure. I'll ask Jackie to comment on this. We saw multiple patients that fit our inclusion criteria here who had previous BCG, but outside of a window that sort of would make them characterize as BCG experience. Do you want to expound on that?

Sure. So in our early conversations with the FDA around the design of this trial and the population that we could include in ADVANCED-2 cohort A, we did align with them on having patients that were exposed to BCG and within 24 -- more than 24 months since enrollment into the trial. So we have a subset of patients within this data set that we're reporting where they were, in fact, exposed to BCG. And some of them had full course maintenance, some were induction only, but the reality was is that this is not a purely just naive patient population. So there is some prior exposure.

And I think that's how you should think about the patient population that we would enroll in the RCT that we've been discussing with FDA and that, again, we would nascently be calling ADVANCED- 3. There, really, what we're looking at is any patient who would otherwise qualify for BCG, but for whatever reason, doesn't get it, refuses, that's an important piece of the population, intolerant to, that's a patient that, by definition, would have already been exposed to BCG or a pure naive patient. I think as you start to think about what that comprises, and remember, in our comments, we said about 40% of all otherwise BCG-ligible patients in the United States do not get BCG. And there's a whole host of reasons why that would be the case. And so when you think about what is the eventual market opportunity, when you are looking at such a wide range of sort of baseline characteristics, that should speak to you of an addressable patient population that, for sure, is larger than BCG unresponsive CIS.

Our next question will come from Andres Maldonado with H.C. Wainwright.

Congrats on the data. Two for me. Maybe one, let's start with Dr. Shore. You mentioned the BRIDGE study, which essentially was, at one point, started to really answer the question, does Gem/Doce work? How has that signal kind of evolved amongst your colleagues? Obviously, we've heard two camps of people that believe in it and others that don't. So removing all the cumbersome administrational hurdles, where do you fall in that camp? And then maybe one for management. Looking at the data set, given the genetic heterogeneity of cyst, what proportion of the data set that you presented today may be consisted of lower-risk cysts, so smaller lesions or focal cysts? And how should we be thinking about that potentially enriching or not enriching the CR percentage compared to what we will see in the real world?

Neal, do you want to take that first question on Gem/Doce, just sort of your sense of how community broadly is thinking about it?

Yes. Yes. So look, I appreciate the question, and I appreciate as many options as possible for our patients, right? And so if you have an efficacious therapy that can be tolerated, that can be administered, that is not economically punitive; and some would argue, quite frankly, that Gem/Doce is in terms of the economic modeling of the practice, many will argue that cost of goods there is really low. That's a completely separate issue regarding the competitive landscape and a separate issue that folks from Protara could certainly weigh in on that I'm not prepared to. So do I use Gem/Doce? Yes, I do. Is it convenient and well accepted by my administrators? No, it's not. Will I offer it to the right patient? Yes, I will. And will -- academic centers where they're set up to have the administration and the biohazard concerns, many community practices, they just ship them off there. That's what they'll tell you when they do it. I mean I'm just being candid about it. There are some exception sites such as mine that will administer it. And I think even my colleagues in AMCs, they understand that, the issues regarding the person power challenges, not just physician, but LPNs, medical assistants, et cetera, and tying up rooms for throughput purposes makes the Gem/Doce argument for wide adoption a challenge.

And then to answer your question, Andres, sort of on baseline characteristic phenotypes, et cetera, look, I think every immune-activating agent that has either been approved or interrogated in the NMIBC setting, we absolutely recognize and have seen across the board that CIS on its own, highly immunoresponsive, considered a high-risk version of the disease and responsive to immune therapies. CIS with concomitant papillary is a different animal altogether. And no matter whose data set, if it's us or one of the other sponsors in this setting, if you're employing an immune approach to that concomitant papillary patient, that is a tougher-to-treat patient population. And you would expect to see lower overall response rates in patients of that phenotype. In this data set, if you look back to what we reported in April at AUA, these exact same patients, the breakout for us of CIS versus CIS with concomitant papillaries was 58%, 42%, respectively. We have not enrolled any additional patients. So you would -- by the transitive properties of numbers, you would then extrapolate that at the exact same mix of CIS versus CIS plus papillary in this data set. Now as you look -- and I know that there are folks that are probably trying to extrapolate from this BCG-Naive data set that we're talking about today, there are some folks that may be trying to extrapolate from this to our BCG-Unresponsive registrational study, where we are anticipating a data release there in the next couple of months. What we have been saying, and you're probably sticking hearing it by now, Andres, we've been saying for some time is that based on driver mutational burden of a BCG-Naive patient and a BCG-Unresponsive patient, we believe that those patients are far more biologically similar than they are different. And our expectation, and we have been very vocal on this, is that over time, you should expect to see response rates in Naive and response rates in Unresponsive that are on 002 to converge. And we do not feel like we have to make any statements or modifiers to that basic core assumption. So when you take that into account, when you take into account that eventually, we anticipate that these patient populations when being administered 002, they would converge over time. And note that as you look at registrational studies conducted by other sponsors in the unresponsive setting, generally, you see somewhere between 70% to 80% enrollment of CIS only. So again, the way that I think about it is at 58% CIS only, this is a study that I would characterize as under enriched in CIS-only patients, given what we see in other studies and how -- where the enrollment is for those patients. And that over time, while we're looking to just have any study we conduct in NMIBC reflect the real-world population, we've now got a sample size of at least 4 other registrationally designed studies in the unresponsive setting where 70% or higher of those patients were of a CIS-only phenotype. Does that help?

Very much. And maybe if I may, one quick last question. Maybe regarding the control arm of the study, just out of curiosity, either for Dr. Shore or the management team here, real-world data, has there been any kind of tangential kind of evidence that patients that may have been exposed to maybe gemcitabine alone, whether it be through intravesical device or other method, can be resensitized with Gem/Doce? Any high-level thoughts there? Just trying to figure out the dynamics here of patients that are -- if one can resensitize the other and how that shifts kind of the market dynamics here.

I'm going to have to defer to Dr. Shore. We -- on the management side, are not aware of that level of dynamic. Sort of if you've had Gem before, if you've had Gem/Doce before, does that change or is that predictive of a differential response in a subsequent treatment? I don't know, Neal, is that something that you've seen?

That's an interesting question. Typically, there are some individual-site data sets. A good friend, Mike O'Donnell at University of Iowa, probably has maybe some of the largest of folks who've come in from -- who've just had Gem or maybe had mitomycin and then went on to Gem/Doce. But I'm not aware of any sort of preclinical work that would demonstrate either increased sensitivity response versus any ongoing resistance on a preclinical side. And then even on the clinical side, I don't know of any large multicenter data sets to look at that. It's an interesting question. But yes, that's about as far as I would take that.

Our next question will come from Charles Zhu with LifeSci Capital.

Congratulations on the updates, particularly on the regulatory clarity. First one from me. Is there an opportunity to expand the TARA-002 market opportunity solely on the basis of patient refusal for those who are eligible and have access to BCG, right? Because that's one of the inclusion criteria for your registrational study. I'm just kind of wondering if one day -- if and when one day you get approved in the setting, if patients just flood up, say, you know what, you have BCG, I can use it, but I don't want to use it for whatever reason. Is there an opportunity really to expand that pie there? And maybe question but from the other side, as you have numerous other developmental therapies emerge in combination with BCG in the naive setting, can you also talk about the pushes and pulls here? On one hand, you got the great safety, the efficacy and the convenience of TARA-002. But maybe on the other hand, you have, let's call it, these combination therapies that will presumably have much better than BCG efficacy. Can you talk about some of the pushes and pulls there?

Sure. So let me take your first one, refusal. And maybe what I'll do is I'll just take a quick moment to sort of lay out almost sort of like storytell a little bit of where we see or what could a story look like in terms of the use case for 002, right? Because I think the question is where does 002 fit irrespective of BCG supply. And so look, the first is a practice like Dr. Shore right now that is experiencing a shortage. You've got 50 patients that qualify for BCG use and may or may not have it. That's an obvious one. I think to your other question, a scenario that we've heard from physicians is they'll have a conversation with their patient and say, "Look, you got a diagnosis of," let's call it, "CIS plus TA, and we want to put you on BCG. I'll put the order in for BCG. And at this stage, what I've been getting is sort of enough to put you on induction, but this is a 2-year course. And I'm not sure that I will be able to get the remaining sort of, let's call it, 18 vials to complete your maintenance course. I can induce you, but I just can't promise based on our flows." And if BCG failed a batch even with ostensibly increased capacity, that means that we're back into a shortage situation. Let's not forget that even when Sanofi and TCE were both in the market kind of around 2017 and before, there were still periods of shortage where both manufacturers could not supply the market. So coming back, the first and most obvious here, as we think about what the addressable population, is BCG is not around and you got 50 patients, just like Dr. Shore talked about. And that will still continue for years to come, even if Merck is able to come online with new capacity. Then there is this other thing where you've got a whole generation of urologists that trained and did their residency and came into the urology specialty knowing and living with BCG shortage. So this idea of I can't predict that I'll be able to get you all of the BCG that you need for the optimal response, I can give you the induction course of BCG. We also have 002, which we have thousands of vials of it in our refrigerator right now. There's an opportunity where the patient and the physician together would say, "Well, I just want to take the uncertainty off the table, let's go with 002." And then to your other question, there are patients who have had BCG before, responded to BCG. 2 years later since their last dose of BCG, there's a recurrence. And if that patient is aware that there is an alternative with pretty similar efficacy, that patient might say, "Great, I know I qualify for BCG, and I'm sure you got a bunch of it, but I don't want to go through that again." So that's another sort of case that literally is a real-world story that we've heard. And then the last that I'd say is a patient on the younger side, who comes in for their first diagnosis and is adamant that they don't want a cystectomy. So now that urologist has got -- let's say, it's a 45- or 50-year-old patient. That urologist is likely thinking, "I got to keep this bladder intact for the next 20 to 30 years." I know that BCG is super -- it's a great drug when it's administered effectively. So let's start them on something else and preserve BCG for a downstream anticipated recurrence because what we know is that if you give these patients a lot of BCG over multiple recurrences, they develop an unresponsiveness or they develop tolerance or refractory. So those are four different sort of scenarios that are among many different scenarios. And ultimately, look, patients that are informed and physicians that are informed make choices based on multiple factors. And I'm sure Dr. Shore can back us up, we would anticipate that at this stage, with what we're showing today, we are through a threshold of relevance from an efficacy perspective, kind of irrespective of the combo studies that we've seen out there in the front line. So at the risk of now talking too long about this, patients will vote based on tolerability, based on reliability. And that's what I believe we offer patients in this sort of BCG eligible unable to get BCG or refuse. You weren't anticipating that, yes, silence. Charles, what else do you have?

Yes. Maybe just one other very quick question here. I may have missed this earlier, but your 69% CR rate at 6 months, could you just very quickly remind us of the 6-month CR rate benchmarks that you'd expect to see from your control arm chemotherapies?

Yes. So look, there's not a lot of great work out there in the literature on [ GE or MYO ]. I think physicians like Dr. Shore that have seen a lot, have utilized these agents a fair amount; would have a view. We are basing our powering on basically claims data that we -- that covers about 7 years of utilization of some of these chemotherapeutic agents. And what I can tell you is, and this is what we've sort of said to folks as we've been teeing up the market for this potential data release, is in general, Gem, you should consider Gem to be somewhere around 40% at 6 months and 15% at 12; [ MITO ], probably somewhere around 35% at 6 and not typically durable to 12. And for the small number of patients that are Gem/Doce patients that may make their way into the study in the control arm, I think the BRIDGE study and some of the work that Mike O'Donnell has done shows kind of what you can expect there. But just a reminder, the large majority of our active sites are our community sites like Dr. Shore's. And I think he's done a pretty good job of laying out how much gem dosing we're likely to encounter as we sort of get this study up and running and enrolled.

Got it. Really appreciate your very thoughtful and comprehensive answers to our questions, and congrats again on this update.

That concludes the Q&A session and the call. Thank you for joining. You may now disconnect.