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

Hello, and welcome to the Protara Therapeutics ASCO GU Update Call. [Operator Instructions] As a reminder, this conference call 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 analysis 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. Joining us on today's call are Jesse Shefferman, Co-Founder, Director and Chief Executive Officer of Protara; and Dr. Carla Beckham, who is a Board-certified urologist and the Lead Medical Director and Head of Clinical Development for the TARA-002 NMIBC program. Additionally, we are privileged to be joined by Dr. Neal Shore, Medical Director of START Carolinas/Carolina Urologic Research Center. At the conclusion of our prepared remarks, we will open the call for Q&A and are joined by our Chief R&D Officer and Co-Founder, Dr. Jacqueline Zummo; Chief Financial Officer, Pat Fabbio; Chief Medical Officer, Dr. Leonardo Nicacio; and our Chief Commercial Officer, Bill Conkling. I will now turn the call over to Jesse.

Thank you, Justine, and thank you all for joining us this morning. We are pleased to share positive interim results from our ongoing Phase II ADVANCED-2 trial of TARA-002 in patients with NMIBC. These data will be presented during a poster session at GU ASCO later this week. Today, we will share interim efficacy and safety data from both ADVANCED-2 trial cohorts, the BCG-unresponsive and the BCG-naive cohorts. Note that the data included in the press release we issued yesterday and the conference posters have a data cutoff of January 2026, and the abstracts that posted yesterday have an earlier data cutoff of October 2025. In both cohorts, TARA-002 continues to demonstrate compelling response rates and excellent safety and tolerability. We believe the interim results in the BCG-unresponsive cohort are exciting with top of the competitive range 6-month response rates and accumulating 12-month data with a median follow-up of 5.6 months in evaluable participants. We are confident given the response dynamics that we've observed in both BCG-naive and BCG-unresponsive patients that 12-month response rates will be a strength for 002 as current 6- and 9-month CRs mature. These positive interim data give us confidence that TARA-002 has the potential to be an important mainstay in the NMIBC treatment paradigm. 002 has a potential best-in-class product profile with compelling response rates, encouraging durability and a favorable safety and tolerability profile. These, combined with its off-the-shelf availability and fast, simple administration, position 002 to easily address the factors that are priorities for NMIBC patients and urologists and provide key competitive advantages within the evolving NMIBC landscape. For those of you who may be new to the Protara story, we are a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases. Our lead asset is TARA-002, which we are assessing in NMIBC as well as in lymphatic malformations, which are rare congenital malformations of lymphatic vessels typically diagnosed in childhood. And finally, our pipeline also includes IV Choline Chloride, an investigational phospholipid substrate replacement for patients dependent on parenteral support. We're excited about the potential for all of our programs to make a meaningful difference in the lives of patients. Today's focus though will be on the updated interim analysis from our ADVANCED-2 trial in NMIBC. TARA-002 has a unique profile in the NMIBC treatment landscape. It 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, mostly mild, self-limited local reactions with no related serious adverse events or treatment-related discontinuations. Additionally, it is administered through a simple office-based intravesical instillation with no viral handling, no special preparation and no burdensome post-administration protocols for patients, making it easy to integrate in existing practice workflows. We believe these product attributes position 002 as a best-in-class next-generation investigational therapy with the potential to meaningfully impact care in NMIBC. I would now like to turn the call over to Carla to walk us through the interim analyses.

Thanks, Jesse. By now you're all familiar with 002's unique mechanism of action. TARA-002 is a genetically distinct [ 2 ] strain of strep pyogenes that drives an antitumor Th1 immunological response. TARA-002 is manufactured from the same master cell bank as the originator therapy, OK-432, which was developed by Chugai Pharmaceuticals and is approved for a number of oncology indications in Japan with an over 65,000 patient safety database collected from clinical trials and commercial use. It is a pleasure to review this exciting data with you. As a reminder, the ongoing Phase II open-label ADVANCED-2 clinical trial is assessing intravesical TARA-002 in NMIBC patients with carcinoma in situ with or without papillary disease who are either BCG-unresponsive or BCG-naive. The BCG-unresponsive cohort is designed with the registrational alignment with the FDA's updated 2024 BCG-unresponsive NMIBC guidance. Participants in the trial received 6 weekly intravesical instillations of TARA-002, followed by a maintenance course of 3 weekly instillations every 3 months. Participants 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, defined as progression or recurrent T1 disease. At the request of the FDA, there was a mandatory biopsy at month 3 in our registrational BCG-unresponsive cohort. Turning to the BCG-unresponsive data. At the time of data cutoff, the complete response rate at any time was 66%, 68% at 6 months and 33% at 12 months. This initial durability is encouraging, especially in light of the small sample size and the inherent challenge intrinsic to landmark analysis with short follow-up. In addition, responders are making their CRs -- maintaining their CRs, demonstrating good potential for a continued durable response. The Kaplan-Meier estimate probability of maintaining a CR for 6 months is 71%. And we see that 100% of evaluable responders maintain their CRs from month 9 to 12. Another exciting data point is the 62% of the participants who converted from non-CR to a CR at 6 months with reinduction. In summary, we are enthusiastic about these initial results. We have seen a steady increase in enrollment in the BCG-unresponsive cohort as we have executed our global expansion and expect to complete enrollment in this registrational study in the second half of 2026. Now for a brief update on the BCG-naive cohort, which is fully enrolled. At the point of data cutoff, the complete response rate at any time was 72%, 67% at 6 months and 58% at 12 months. This 12-month response rate marks a significant improvement from the observed at previous data cutoffs. We are pleased to see the 12-month CR continue to increase as longer follow-ups occur. In addition, TARA-002 shows good signs of durability in BCG-naive patients. The Kaplan-Meier estimated probability of maintaining a CR for 6 months was 73%. In addition, 100% evaluable responders maintained their CRs from month 9 to 12. Importantly, 67% of reinduced patients converted to complete response at month 6. We are pleased with the strong results in BCG-naive participants. As urologists, I'd like to think about how these data inform our understanding of what we can expect from TARA-002 in the BCG-unresponsive cohort as it matures. The 3 pillars of the clinical profile are efficacy, safety and tolerability. TARA-002 is well tolerated in this older population with significant medical comorbidities. Furthermore, we think that the clinical profile, coupled with the ease of use and low burden on the patient, physician and staff will lead to a preference for TARA-002 in the real-world setting. 002 continued to show that the majority of treatment-related adverse events, which included dysuria, bladder spasm, fatigue and urgency were Grade 1 and transient and none were grade 3 or greater. In addition, no participants discontinued treatment due to related AEs. Overall, the efficacy and safety of TARA-002 observed in both the BCG-unresponsive and naive populations are promising. And we look forward to completing enrollment in the BCG-unresponsive cohort and starting the ADVANCED-3 registrational trial in BCG-naive patients later this year.

[Operator Instructions] We'll take the first question from Stacy Ku with TD Cowen.

Congratulations on the impressive 6-month efficacy. Of course, now that we have the 6-month results, our attention does turn to the 12 months durability data. So just given your comments on 002 historically and the expected performance in BCG naive and BCG-unresponsive NMIBC patients as we look to the summer plot and as the 12-month data matures, first question is, would you expect the CR rate to improve? And then as a follow-up, maybe elaborate on your observations regarding some of these early responders, patients that are achieving CR at maybe the 3-month time point and your views on durability. So that's the kind of first 2-part question. The next question is more on timing, if you're all willing to give us some type of guidance as to when we could get the next data update for ADVANCED-2. And I can wait for Dr. Shore to connect for my last question.

Okay. Well, thank you to everybody for bearing with this technical glitch, never a dull moment. So I'll take -- so first, Stacy, thank you for acknowledging that the 6-month number here is -- it's something that we're very proud of. Our view is that we've got just about the best landmark CR rate that has been published to date amongst our peers at that time point. I think what matters is -- and again, drawing everybody back to a common refrain from Protara, which is that as the data sets mature in both cohorts A and Cohort B of the ADVANCED-2 study, we expect that the data will converge. And really, our underlying view is that prior BCG exposure is not as important as, frankly, degree of pretreatment of patients in the unresponsive setting, the number of pretreatments. And so again, as you -- I think this data, as you look at the 6 months either CR at any time or landmark CR across the 2 cohorts, you've seen that, that has happened that those numbers have converged. Look, I think the number at 12 months is a function of a small sample size, which I think by now, everybody on this line that's been looking at the oncology space for some time knows that landmark with low N is typically unfairly biased by early nonresponders, which every study has and not sort of benefiting from the green dots that you see here that have not made it yet to that 12-month evaluation time point. I guess as -- just keeping this swimmer's plot slide up, Stacy, as you start from the top, every green dot at the 3-month time point tends to be a green dot at 6 months and again, still at 9, there are a few that aren't. But then once these patients get to that 9-month time point, they have a 100% probability at this point of maintaining that CR. So then as you go down the swimmers plot, you see that there is a bolus of green dots at the 3-month time point, which if that dynamic maintains, they have a fairly high probability of becoming 12-month CRs. But look, you don't even have to go to those 3-month CRs. Just look at the next three 9-month patients that are just there towards the top. Right now, we would anticipate that at least a significant percentage of those patients, if not 100% based on our previous experience, would convert to CR. So look, that's a lot of sort of pick [indiscernible] to try and get at. We are very confident that the number that you see today of our month 12 CR rate will be in the 40s by the time this data set is full, right? I think making a call on durability on the first 15 patients of a 100-patient study is not something that guides our decision-making, and we would posit that it probably shouldn't guide others' decision-making as well. Remind me your second question, Stacy?

Timing for the next data update for ADVANCED-2.

Look, I think as it relates to our next update, if you take a look back over the past 3 years, we've been on a pretty steady cadence of trying to provide something for investors at major urologic conferences. I think to us, those conferences are GU ASCO, AUA, increasingly ESMO and the SUO conference towards the end of the year. So we're not prepared yet to guide on when the next time we would release data would be. But obviously, these -- the naive patients in Cohort A are going to continue to mature and will continue to provide, I think, a breadcrumb trail for what to expect as the unresponsive arm matures. And obviously, we are maintaining our guidance that we'll be fully enrolled in the unresponsive arm by the end of the year. And I can say that, I think, with a measure of comfort. And so as a result, I think you can just sort of look to the medical conferences as where we have historically provided data. And our objective will be to provide answers as they are available and interpretable on that 12-month durability number.

Okay. Understood. And I don't know if Dr. Shore is back and connected. I do have a question for him, but if not, I can wait and hop back into the end of the queue.

Well, he says he's trying. We're going to keep going, Stacy. If you want, you can pop back in after we get Dr. Shore back on. Thank you, though.

Our next question comes from Leland Gershell with Oppenheimer.

Congrats on this update. My questions would await Dr. Shore's rejoining. So I will defer until he's back on.

Our next question comes from Kelsey Goodwin with Piper Sandler.

Congrats on the data. I'm going to ask my non-Dr. Shore questions and maybe can hop back in the queue with the rest of the analysts as well. But maybe just remind us, for this unresponsive cohort, were the patients allowed to see experimental agents prior to joining the study? And how does that compare to competitor data sets and kind of shape what we're looking at today? And then a second question, maybe just for the benefit of us all hearing it, a question I get asked very frequently is how your definition of high-grade CR compares to the use of just more broadly CR that the competitors use in the high-risk space. So maybe you could just clarify that for us as well.

So the question that I heard is degree of sort of other investigational treatments that we've observed and then how we're defining CR, Kelsey. So I guess I'll take the first one. Look, I think given where we are sort of in the -- sort of the time horizon of investigational agents that have sort of emerged in the last several years, you've got a number of marketed products and that are on the market, and you've got a number of other sort of investigational agents. I'll give you the numerical answer. But what I'd like to sort of highlight is at this particular moment, as you are enrolling CIS patients, the probability goes up that the patients that you have enrolled are recurring from not only BCG -- prior BCG treatment, but a number of others as well. So about 35%, Kelsey, of the patients in this data set were treated with other either investigational or approved products. So every -- I won't sort of name names, but these patients have seen everything from Gem/Doce. They've seen checkpoint inhibitors. A number of them have seen both kind of targeted immunotherapies that are either approved or about to be approved ostensibly, and they've also seen sort of enhanced chemotherapeutic agents. We've sort of seen the gamut there. So -- and I think that, that speaks to the quality of these responses is that, that's a pretty high number of kind of previously treated patients. And look, I don't have and I don't think anybody on the line from our team has at their fingertips sort of an array of level of pretreatment from some of the competitive products that are out there. But I think you should sort of as a rule of thumb, kind of think that as folks like Protara and others who are still kind of wrapping up their pre-registrational studies, that those agents will have seen some measure or some number of prior treatments with kind of what we would consider to be competitive branded products. And so then as it relates to kind of the definition of CR, again, what I would say is we, as a rule, really try to hew as closely as possible to FDA guidance wherever they make it available. And so we just simply use high-grade CR as it's defined by the FDA, which means any high-grade recurrence. So high-grade disease is either CIS, it's TA, it's T1 or it's CIS plus TA or T1. That is a high-grade recurrence. What is not a high-grade CR is any low-grade recurrence. It's our understanding that if everybody is hewing to FDA guidance, all of the protocols for kind of investigational or recently approved products allow for resection of low-grade disease, and that would not be a cause, for instance, at the 3-month time point for reinduction. So that is not considered a high-grade recurrence. Again, our understanding is that that's what -- that's how everybody kind of defines CR. And again, it's how the FDA wants to see it. So that's how we're going for it. Do we have Dr. Shore back on the line?

Yes. Jesse, can you hear me?

I can. Well, Neal, I think we can sort of move from your prepared remarks unless you have a couple of things that you'd like to say about your experience with 002 because you got a lot of questions from our listeners.

Yes, sure. Thanks, Jesse. Apologies to everybody. I think the bomb cyclone of the winter storm, it's over my house. The good news is that I have had -- I really -- I've had the privilege as a GU oncology researcher and not just in prostate, but in bladder in the last 8 years for both NMIBC naive, unresponsive and [ MIBC ] to be privileged to be part of most of the trials that I'm sure you're all familiar with. And it's been a great privilege because we've made such great advances. I will just kind of -- that's my background, and I'm the Director of START Carolinas. I head GU Oncology for START Cancer Research. And I was one of the original founders of the bladder cancer think tank and was on the Board of BCAN for over 10 years. I'm excited to go out to ASCO GU. I'm happy to be the senior author on 2 of the posters that are getting presented that was really the crux of the call today. They're really great swimmers plots as you've seen. So I'm happy to answer any questions from the folks listening in, and I apologize for the technical mishap.

Great. So operator, if we could reopen the queue. I think there are a number of folks on the line that have questions for Dr. Shore.

We'll take the first question again from Stacy Ku.

Hopefully, you guys can hear me okay. Dr. Shore, so I was curious what your view is on the salvage rate for TARA-002. So just help us understand how important that data point is and taking the totality of the results as urologists consider the different treatment options. So just a question on salvage rate and how competitive it is.

Yes. No, I think it's a great question. And of course, we oftentimes see salvage in some therapies, not in all therapies, it varies per protocol design, but the salvage rates that we see here are remarkably impressive. I think, as was alluded to earlier, the simplicity of the delivery, which cannot be overemphasized given the challenges we have, not just in academic, but in community centers, reinduction will be highly appealing to patients and physicians and the team because of the really -- I don't -- it's always a challenge to say best-in-class, but certainly arguable that their safety profile and the extensiveness of the database going back to OK-432 and now with 002 is so well tolerated. So if somebody needs a reinduction, I don't think there's going to be much pushback compared to what we've seen with some other therapy. So the high reinduction success baked into your question, I think it makes it remarkably compelling.

Our next question comes from Leland Gershell with Oppenheimer.

Great. Dr. Shore. So I just wanted to ask, as we step back and we look at the interim efficacy data here and then efficacy data we've seen from other agents. I mean in the medical oncology setting, where there may be less differences amongst agents in terms of their other factors like tolerability and so forth, folks are keen to kind of put a high sort of focused on even slight differences in efficacy rates. Here, we have efficacy rates that are all kind of generally comparable, but there are advantages seemingly to TARA-002 versus some other therapy. So I wanted to ask how are you going to think as a urologist [ as well as an ] oncologist about treating patients with 002 presuming it gets approved versus other agents, either in kind of a sequence format or in a stage of disease format. And also want to ask with respect to sort of the view that there are agents that may be available and some are already available in the market that may have kind of a first-mover advantage, let's call it, to Protara. How much does that matter as Protara comes to the market?

I appreciate the question. One of the slides I thought that Jesse presented early on, I think it was in sixth slide, I sort of love that Venn diagram where you saw 2 in the center of safety, efficacy and simplicity. There's no doubt. And within your question, I really liked it because look, 95% of patients don't want to go on to become -- well, 100% don't want to become unresponsive. And then those who are unresponsive who are looking for their first line of treatment, they 95% don't want their bladders removed. So within the construct of your question is -- and in the U.S., we have this proverbial embarrassment of riches unlike anywhere else in the world in the unresponsive state. You have multiple different options, whereas outside of the U.S., it's basically a single agent chemotherapeutic and/or bladder removal. So I think the sequencing or what some have called the stacking of therapies is really ubiquitously practiced within community and even arguably in academic centers. Of course, more sophisticated uro-oncology centers such as mine and others, we may be more likely to go for some therapies that have higher AE profiles. But I think that given that we know that 80%, 85% of cancer care NMIBC, naive or unresponsive is happening in the community where safety, possibly simplicity, with comparable efficacy is going to really win. Now you're right. I mean, there is always the possibility of first-mover advantage, but I frankly have not seen that being as durable as you would expect given the really frothy burgeoning nature of NMIBC.

We'll take our next question from Kelsey Goodwin with Piper Sandler.

My questions for Dr. Shore have been asked.

We'll take our next question from Li Watsek with Cantor.

I want to add my congrats on the impressive 6-month CR rate as well. My first question is on the trial itself. I wonder if you can share a little bit about maybe the patient baseline characteristics, particularly in a proportion of patients with papillary disease.

Li. Yes, we in the appendix of the slides that we posted, you could see that we had a high percentage of CIS-only patients. That is not by design. It's sort of how the patients have enrolled. I think as we continue to go towards full enrollment, we know that we've got to keep kind of about 20% of the study comprised of concomitant papillary patients. I think to kind of be in the same ballpark as what we've seen others present as a registrational data set. So what I can say, though, is this is our observation as we have now dosed kind of 90-plus patients with this agent is that concomitant papillary tends to -- or versus CIS only tends to be more impactful on early response. As we have looked at -- obviously, look, I mean, we acknowledge that durability at this point remains the only outstanding question on 002 because we've certainly answered kind of the 6-month number, which is what everybody else has made hay with. I think now that we've proven that point, we're looking at durability. And what we know and what we've observed is that concomitant papillary status doesn't really convey an interpretable through line to that answer of what is the durability. It's far more important for your 3-month and 6-month response, very much not as important, again, across 90-plus patients for that durability. I think you got to have 20% concomitant papillary in your data set to have a label that says CIS plus/minus Ta/T1. I'm confident that we'll get there just knowing kind of what comprises some of our earlier not yet 3-month evaluable patients. Look, I think we have not managed our CIS versus CIS concomitant status to date. But as we get closer to full enrollment into the second half of the year, if we have to, then we'll go back to our sites and sort of kind of like, I guess, reaffirm the fact that we need to see them enrolling a relevant number of concomitant papillary patients.

Great. My second question is for Dr. Shore about adoption. Obviously, you talked a lot about the importance of safety, ease of administration, especially in the community setting. So I just wonder if you can just give us your view in terms of 002's degree of differentiation on these aspects relative to the other options? And how would you rank these factors in terms of driving adoption? Obviously, for a lot of investors, they tend to focus more on the efficacy side as a primary sort of factor, but it seems like in this setting, maybe safety and administration could be equally dominant driving forces.

Sure. Yes. Thanks. Appreciate the question. And you're right. I mean, sometimes it seems that our focus is just trying to look at hazard ratios on efficacy with small data set. But what I really like about what the folks at Protara are doing is they recognize the importance of expansion of their data set and durability, which I think is looking very promisingly. When you think about the crux of your question, this is never going to be a supply chain issue as you see with BCG. And there are some other very important aspects to the competitive environment. There are certain types of safety equipment ranging from hoods and genetic and viral protective safety measures that have to be invoked for some of the therapies that are out there and not all sites, frankly, are up to the task for that. So that's super important. And then even some things as simple as do you have freezer capability, do you own the equipment, do you have the storage for it? That's not an issue for 002. These are really important operational challenges and safety requirements. Additionally, as was stated, and it shouldn't go without attention from a strategic marketing standpoint is the just in time -- there's no just-in-time delivery. This is truly off the shelf product, which, in addition to the comments on safety and patient tolerability. As everybody on this call knows, and it's not unique to NMIBC or MIBC or prostate or bladder or kidney cancer, which is what I deal with, but there are person power shortages and there are supply chain issues that are really burdening the health care system. So I think 002 fits in really well with that regarding the landscape. And then the other thing that the efficacy data is very compelling, as you've already seen, that's why it's exciting to see these 2 posters coming forward. But also, it does have a unique MOA. So it's really very consistent, but a little bit simpler in terms of being an immunopotentiator as is BCG, which goes into the historical understanding for urologists, general urologists as well as for uro-oncologists.

We'll take our next question from Andres Maldonado from H.C. Wainwright.

Congrats on the data again. I guess one for Dr. Shore. You touched upon that there are some more advanced therapies that are ahead of Protara. So in that light, so say, one proportion of those patients get a viral or non-gene therapy, the other proportion may get an intravesical chemo device. How does the algorithm change of treatment between the 2 cohorts of BCG-unresponsive and BCG-naive? And then I guess, more importantly, for those subsets, how close are we to painting a picture of patient characteristics such as cyst burden or prior BCG failure or time since last BCG to really get some traction on an algorithm that really affects these patients most effectively?

Yes. No, thanks. Appreciate the question. The -- let me take -- sort of a bunch to unpack there. But the last part of your question was addressing this BCG exposed population, which is a remarkably large population and it basically creates a sort of certain conundrums as we try to enroll patients in those who had less than an adequate induction or 5 plus 2 per FDA working group and/or they had BCG way north of 12 months prior to their recurrences. So that's a big population. And I think ultimately, where there are shortages of BCG, which is a sort of a metastable issue in the United States, who knows how that's going to play out once the new Merck plant comes online. No one can ever be completely certain of that. Again, it doesn't appear that there should be ever an 002 shortage. The other thing that comes into play, and it's certainly not my expertise, but understanding the cost of goods being particularly low, when therapies come out and in our ever-changing health care reimbursement schedule, practices, particularly the nonphysician leadership will look at the outlier of purchase and the reimbursement based upon where we are, whether it continues to be under a Part B structure and typically looking at your ASP 6% or 4.4%. So that's basically a little bit of a long-winded way of saying the practices, and I'm seeing this more and more in academic centers, there is push towards understanding what the urology clinic practice will have to put forward in terms of purchase and what they can expect in terms of their reimbursement. So I think that the structuring or the sequencing or the stacking is going to most likely be the sort of wanted concept of shared decision-making, which we all talk about. I'm a big proponent of it. And when you have multiple things to choose from, what will the percentage of Grade 3, 4 adverse events be of one versus another, the time to come into the clinic to receive therapy and the schedule of events and whether or not it's a monotherapy versus a combinatorial therapy and then all the other safety and equipment issues. So I think that, that is going to have an enormous impact on the BCG naive. Once you get to unresponsive and then you're sort of -- the clock is ticking faster and you're more concerned about having your bladder removed, I think then patients and caregivers and health care providers will have a more full throated discussion about efficacy versus safety tolerability.

And maybe just one quick follow-up. I guess, for Dr. Shore. Through the lens of immunological exhaustion. Do any of these therapies particularly stand out to you where 002 might be able to reengage the immune system? Is immune exhaustion something that's on your mind as you're looking at all these next-generation therapies and how to sequence them?

It does. And look, immuno-oncologic understanding whether it's the innate and adaptive pathway, which you saw in that study schema, 002 does impact both innate and adaptive pathways. So for those of us who really love the wonky nature of your question, which I do love it, and it's great, probably less impactful within the community. But I do think about the unique MOA for 002 and even potentially how it could be used in combinatorial strategies with other therapies.

Our next question comes from Charles Zhu with LifeSci Capital.

Congratulations on the data. I've got a couple of quick questions for you. First one, I think you had mentioned that about 35% of your BCG-unresponsive patients in -- unresponsive patients in the data set were treated with other investigational or approved products. Any color around potential differential CR rates for TARA-002 between patients that have versus have not seen some of these other investigational approved products? That's number one. And number two, just visually looking at your swim lanes, big swim lanes by the way. But I'm kind of wondering, it seems that for whatever reason, your BCG-naive patients, there seem to be a lower proportion of 3-month non-CR patients that are being reinduced. Any color as to why that might be the case?

Yes. So I think on the first point, as I said, on the unresponses, you're looking at 43 swim lanes here, of which, let's say, about 35 have sort of been -- have achieved a time point at which we can evaluate them. So look, I mean, 35% of 35%, you're talking about fewer than 9 patients, Charles, that have seen kind of -- I'm sorry, around 9 that have seen kind of -- if my math is correct, so early for me to be doing mental math. Whatever the number is, it's -- there are too many sort of -- I guess, too many versions of that in these swim lanes to sort of start to draw conclusions. It's a handful that have seen Gem/Doce. It's a handful that have seen investigational products that are kind of not yet approved. I can say that it doesn't -- this does not include a prior [ Inlexzo ] failure, but it does include other investigational agents. It does include PD-1 failures. And there are a handful -- I'm just -- we follow each of these patients pretty closely and still it's a small enough and it's getting to be a point where it's not the case, but the end is still small enough where you kind of -- each patient's narrative kind of stands out. And there is a patient in here that I won't identify which one, but that patient failed BCG, of course, then Gem/Doce, then Keytruda, then another agent that we -- is still in the clinic. And that patient achieved at least a 6-month response. So too soon to sort of draw conclusions. But I think that's, again, as Dr. Shore kind of noted, and I don't know that we spend enough time talking about this, ours is the -- 002 is the only broad-spectrum immunopotentiator being interrogated in any form of bladder cancer beside BCG, right? It stands alone in its unique mechanism. And that broad spectrum, right, that sort of multiple lines of attack that is -- and response that's sort of well conserved between the species of strep pyogenes and Homo sapiens, right, like that really super well-conserved immune point counterpoint is encouraging because it's sort of -- what we've observed is so far, again, too soon to tell, but it kind of doesn't matter what the previous thing is that these patients have failed. They all kind of tend to -- the response dynamics tend to be the same. I think as the data set gets closer to 100 and we've got kind of good follow-up, we'll start to be able to talk about, is there a -- if there's a there that helps the world kind of -- or supports where 002 sits, obviously, we're looking at the frontline setting with the Cohort A and ADVANCED-3, that's where we kind of want to be for patients and for providers. But we'd like to be able to, in the future, talk about how 002 is likely to respond following specific prior treatments. And that was so long-winded, Charles. I forgot your second question. Can you hear me with that again?

Sure. Of course. The second question is visually looking at your swim lanes across the BCG-unresponsive and naive. So if you look at the 3-month non-CR patients, it seems that a greater proportion in the BCG naive cohort -- or I should say, a greater proportion of the BCG-unresponsive cohort were able to be reinduced. And can you just help us understand why those proportions seem to be different, the number were actually going through or the proportion going through reinduction?

Yes. It's a function of the mandatory biopsy at 3 months, Charles. So just so that the listeners are aware, we're the only sponsor out there with a mandatory 3-month biopsy. And I think that, that directly correlates to the number of patients that are reinduced. The reason is, in our conversations with FDA about that 3-month biopsy, they asked us to do what's called bladder mapping, which is -- and Dr. Shore speak to this, you take samples of tissue from all over the bladder, not just where the index lesion or the site of lesion that you are there to treat exists. And remember, this is a super recurrent disease of the urothelium of the bladder. And so if you are taking microscopic samples from all over the bladder, you're going to find microscopic disease. And this is where I really want to highlight the difference between the naive and the unresponsive. We do not have a mandatory biopsy in the naive. We do in the unresponsive. And we are capturing disease in those biopsies that is likely months, if not years away from becoming active disease. And so as a result, you're seeing more patients requiring reinduction. What we know from our physicians and perhaps Dr. Shore can speak to this, is it's very rare that a 002 patient is just a null responder. What we observed for these patients at the 3-month time point that aren't quite all the way to disease-free status, you've seen significant tumor regression in all of these patients and sort of the way that some of our investigators characterize it is they needed like a little boost just to get over the hump. And some of those patients, if you look at our naive cohort, and again, if you're willing to come along with us that these 2 cohorts, the dynamics of response are fairly similar, if that disease that we're capturing was near term likely to be active, then you would see a lot of 6-month failures in the naive, but you don't. The greens tend to stay green. And if you come back to the unresponsive swim lanes, we get what is your degree of confidence that, that number right now as the end goes up, will potentially get into the 40s. And from my perspective, as I look at these, our prior patients treated, 85% of a green dot at 3 months is a green dot at some further out time point. We have one 9-month failure amongst the sort of 3-month responders at the top of the swim lanes. So that's a lot of chew on. I'll leave it there.

Our next question comes from Soumit Roy with JonesTrading.

Congratulations on the data again. A quick one on the screen failure rate. If you can provide us any color on the BCG-unresponsive and the BCG-naive cohort, what percentage is for advanced papillary or any other BCG exposure or any other parameters?

Yes. Soumit, at this point, we're not disclosing kind of screen failure details. What I can tell you is that we are not spending a huge amount of time kind of looking at different patient phenotypes. The sites at this point, we've got enough sites up that they are facile in sort of identifying patients that are appropriate for the study. But what I can tell you is we are the only sponsor out there that requires central confirmation of active disease at baseline. That's a big deal. And I would argue that, that probably contributes to a screen fail rate for 002 that is higher than our peers because, again, that extra step of confirming active disease by central reader, that adds a layer of complexity to the screening process.

Got it. And the second one is as we are -- everybody trying to figure out the durability at 12 months, there are like patients at 6 months is -- I'm looking at the unresponsive in swimmers lane, but there are like 5 of them discontinuing. Anything specific for these discontinuing patients, whether BCG-unresponsive cohort or naive-cohort that stands out leading to this discontinuation?

Not really. I mean we don't see any specific disease characteristics or any relation to BCG status as it relates to whether or not a patient responds. We've conducted pretty extensive responder analyses at this point to try to look to see whether durability is predicted by any specific clinical characteristic or baseline characteristics, and we see that there's nothing that really predicts that.

Got it. And last one is if there is any evidence that as you're looking at the data that may suggest underlying mechanism of resistance to BCG that could affect TARA-002's efficacy?

No. I mean we've got patients that have been heavily pretreated, have failed multiple rounds of BCG. And in fact, most of the patients in this population in the unresponsive setting have received more than 12 doses and have had more than one sort of course of BCG that's adequate. So I don't think there's anything that we see in patients that have had less than that, that changes the response dynamic. In fact, I think, as Jesse mentioned earlier, irrespective of whether or not they are receiving multiple lines of prior treatment, obviously, that's after they're considered to be BCG-unresponsive, we're still seeing response rates. So I think it's really -- it's agnostic to any specific mechanistic reason for BCG failure.

This concludes the Q&A session of the call. I would now like to hand back over to management for closing remarks.

Thank you, operator. And a special thanks to Dr. Shore for his time and all your comments. To conclude, listen, in our view, the value proposition for 002 in NMIBC is pretty clear at this point. It demonstrates competitive safety and efficacy data. There's an ease of administration advantage that's obvious, and we know will resonate in community practices like Dr. Shore's. Reminder, approximately 80% of NMIBC patients are treated in the community. And so that is where we're really focusing our efforts in terms of preparing the market for Protara's eventual hopeful approval and launch. There's a significant unmet need for new treatment options in the unresponsive and the naive settings. You've heard that today. And obviously, today's data bolsters our confidence that 002 represents a meaningful new treatment option for these patients. We remain laser-focused on execution here at Protara. The goal is to benefit patients. And so while today's update represents another exciting development for our company, most importantly, it represents a potentially groundbreaking development for many patients and caregivers hoping for new treatment options in high-risk NMIBC. So thank you all for joining today's call, especially to our investigators and the patients that are in the study and that have been treated with 002. We appreciate their contribution. We appreciate their families, and we appreciate our investors for supporting us and coming along on the journey with us for 002. And with that, we will close today's call and wish you all a comfortable day of shoveling out from the snow.

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