Okay. Good afternoon. Thanks so much for joining our TD Cowen's Fifth Annual Oncology Innovation Summit. I'm Stacy Ku, one of the biotech analysts here, and I'm joined by my colleague, Vishwa Shah. So we'd like to welcome Jesse Shefferman, CEO of Protara. Thank you so much for joining, and also a quick thanks to Justine O'Malley, head of IR, who should also be listening in. So we have a lot of moving pieces in the bladder cancer space these days, but just very briefly, for some quick introduction, do you wanna just provide some background on TARA-002 before we kick it off to some questions? Sure. So TARA-002 is a genetically distinct strain of Strep pyogenes that was first immortalized in Japan in the 1960s. It was later taken over by Chugai Pharmaceuticals, where they developed a manufacturing process that engineered out the streptolysin toxicity. And so this version of Strep that we are still deriving from that same master cell bank is completely inactivated. And within the range of options that are sort of in development or approved for NMIBC, it's the only sort of, what we call broad immunopotentiator, besides the sort of standard of care for first-line or frontline therapy, BCG. Okay, wonderful. So, April, you and the team presented some additional updates- Mm-hmm ... that, that we believe establishes proof of concept for TARA-002 and NMIBC. So just walk through the different, efficacy, groups- Mm-hmm ... what data you've seen within each subgroup, and which part that you think is kind of most compelling of the three-month efficacy data that you've presented so far? Sure, sure. So as you mentioned, in April, we presented pooled data from 16 three-month evaluable patients across our NMIBC clinical programmes. These were patients pooled out of our Phase Ia dose escalation that were evaluable at three months, our Phase Ib expansion, and the naive cohort from our Phase II, uh, ADVANCED-2 study. In that data set, nine of the patients were BCG naive. That's the first time I think anyone's put any sort of data out on naive patients, as monotherapy anyway. And seven were BCG experienced, of which two were inadequately treated, so they had only received their induction course, and the remainder were the classic definition of BCG unresponsive, which is at least five doses of induction and two doses of maintenance. And so just to sort of break out, you know, what was the most compelling across all patients, the patients who were CIS only, in other words, did not have concomitant papillary disease, and those CIS-only patients, we produced a 63% complete response rate at three months. And then, you know, as we look at the other sort of, you know, patient subtypes, the BCG unresponsive patients across all of those, whether they were CIS only or had concomitant papillary, at three months were 43% complete response. So our view is that, you know, because of the distinct mechanism of action of 002, the three-month numbers are really the floor of efficacy that we would expect to see. 002 has a delayed onset of therapeutic activity, and once it does achieve its sort of peak therapeutic level, it tends to drive a fairly sustained response, and we've observed this in multiple non-human studies. So, as we look across the, you know, the profile of the patients that were pooled in that analysis, I think 43% is a really, you know, solid baseline from which to improve. You know, you've seen with whether, you know, across multiple competitors in the space, that if you are using an immunologic approach in NMIBC reinduction and rechallenge, for patients that are eligible and who are not complete responders at three months, is a pretty big part of the puzzle, and it will be the same for us. You know, we have continued to enroll patients and have, you know, begun to accumulate patients who are valuable at six months post reinduction or otherwise. You know, we're fairly confident that reinduction will drive enhanced, you know, longer-term response rates, whether that's six months CR at any time, or even further out, like, you know, nine or 12 months. Okay, wonderful. You, you talk about three months being the floor of efficacy and, and, and, you know, how important the reinduction and rechallenge aspect of TARA-002 will be. But do you wanna talk about other key learnings as we thought- as we think about kind of TARA-002 clinical development moving forward? How should we think about kind of the CIS, Ta- Mm-hmm ... T1 patients, versus kind of the CIS-only- Mm-hmm ... general population? So I think a couple of things that we pulled out of our, you know, data and our observations of the patients that we treated. I think the first is, of the eight concomitant papillary patients that were non-CRs at three months, five of those were persistent CIS. In other words, they had undergone TURBT for their papillary disease. That did not recur, and what was left was effectively a CIS-only patient in five out of eight cases. Given the very high response rates that we saw in the CIS-only population, you know, if that pattern continues as we, you know, broaden our enrollment in ADVANCED-2, then you would expect that those patients would be responders after reinduction, based solely on the fact that, you know, our response rates in CIS only are quite high. You know, CIS with concomitant papillary is difficult for everyone. If you sort of look at enrollment rates of other sponsors out there with investigational programs in NMIBC, you know, the preponderance of enrollees are CIS only. You know, I won't name names, but you know, across the competitive landscape for either Phase III studies or, you know, studies that led to approval, you know, you're seeing about 60% to as high as 80% enrollment of CIS only. And as we expand beyond these 16 patients that were sort of a, you know, a mix of different studies and really get into A, international locations, and B, just broaden the number of patients that we're looking at, we would expect to see the same sort of pattern in our enrollment rates as well. Okay. Understood. So I think other learnings that you all had talked about in the past was two additional cohorts- Mm-hmm. -so you're obviously going after a higher dose, 80 KE- Mm-hmm, mm-hmm. ... and then you're also pursuing a priming procedure. So do you wanna just talk about kind of your thoughts around advancing these cohorts? What are you hoping to understand, and- Sure ... how do you plan to, I guess, a three-part question: how do you plan to integrate these potential learnings into your ongoing ADVANCED-2 study, most importantly? Yeah. So I think, look, it will be not a surprise to anyone listening or who is familiar with the landscape that, you know, whether it's because of epidemiology or because of competition, BCG-unresponsive patients are hard to come by. They're certainly out there and, you know, we are enrolling them, but they are harder to come by. And so as you think about exploratory cohorts, the last thing you really... well, the last thing we really wanna do is cannibalize our enrollment of that, of our, you know, unresponsive arm because that's designed to be registrational. The FDA confirmed that they're still accepting single-arm open-label design based on the 2018 guidance as, you know, sufficient for registration the last time we were in front of them. So, you know, we wanna make sure that as we are exploring these alternatives, that we're doing it in a population that we can afford to enroll. And so for us, we're looking at the naive population, which, you know, enroll for us, we are enrolling naives, you know, very, very quickly. I think there's a lot of belief in the investigator community that TARA-002 represents a really good alternative potentially to BCG in that frontline setting. And so we'll look at 80 KE, you know, in the second half of this year, we'll start that study, and then the same for the priming dose. Now, priming for us. Look, 80 KE, I'll take that head-on. You know, look, we did not hit an MTD in our dose escalation. We observed that we were in a therapeutic window, based on responses in that dose escalation, but the FDA asked us to continue to escalate dose, and we've done that. And that should clear, 80 KE should clear safety sort of in the middle of the summer. And that's an option for us to look at. You know, is it just that, you know, we can afford to titrate up a bit on dose? What we're very interested in, though, is the priming element of the second exploratory cohort, what we're calling Cohort D. As you think about other immunologic agents out there that are in the NMIBC space, you know, it's very difficult to, except for perhaps the checkpoint inhibitors, administer those systemically. But because TARA-002 is inactivated and the majority of its utilization in Japan was systemic, for solid tumours, that's a real advantage for us to be able to incorporate systemic dosing. I think when we first, you know, got this program off the ground, Stacy, we, you know, adhered to the Lamm protocol because, you know, I think we sort of just figured that we were a Th1, you know, pro-inflammatory response that was very similar to BCG. But as we dosed more and more BCG-unresponsive patients and got results, we realized, and have gone back now and done the mechanistic studies to bear this out, we're very different from BCG. And a big piece of that means that we don't necessarily need to adhere to the Lamm protocol. As we've learned that we're less and less, we're sort of cousins to BCG, if you will, and at one point, I think we thought we were siblings, but that gives us a lot of degrees of freedom. So priming is interesting, taking it all the way back to these, you know, concomitant papillary patients. You know, there's a few different theories out there for why TA-T1 concomitant with CIS is a tougher-to-treat patient. You know, just by virtue of the fact that they have two different tumor types, you know, makes them tough, tougher to treat. Our observation is that if you could accelerate that delayed on therapeutic effect that I described earlier, those sort of specific kinetics that 002 has, with a priming dose, that, that might, you know, fast-track your responses and keep patients, you know, sort of in a, in a therapeutic window, if you will, and get them there earlier. And, you know, because, again, it's inactivated, we don't- we're not limited to a single priming dose. We can think about multiple systemic administrations. So you start to think about ways that you can be creative in a field that is often limited by intravesical administration. And so, we've got to run a few, non-clinical studies to make sure that we're working with the right priming dose, as well as the right priming interval. But, you know, those will be complete by the middle of the summer, and then we'll start thinking about implementing the human studies. ... Okay, wonderful. And you're making it, you made an interesting point about BCG-unresponsive patients and how you're not BCG-like. That's something that our clinicians had commented on ahead of the data, which is, BCG-unresponsive patients, as kind of well-expected, do not do well with readministration of BCG. Whereas BCG inadequate responders or the kind of experienced group, for you all, you're seeing superior kind of responses to- Yeah ... a second round of BCG. So that is an interesting piece, perspective that our KOLs have commented on. Yeah. Okay, okay, understood. And then to our last question and to our point where you said you don't wanna cannibalize enrollment of your ongoing ADVANCED-2 trial, if you find that the 80 KE tri- you know- Yeah ... you know, dose, obviously, we're gonna be looking at it in naive patients, so that's- Mm ... that's a really good point that you, that you made. But even if you're seeing something interesting there, does that mean that you are then going to go back to your ADVANCED-2 trial? And is there anything kind of written in your, I guess, protocol that allows you to take it, take the dose up? Yes, so yes, I'm very grateful to our clinical staff for having the foresight to write into the protocol an option to escalate dose to 80 KE. So that's actually been, you know, pre-baked into our current protocol. And, you know, I think what we'll do, as you might remember, Stacy, we're gonna put out a 10-patient risk-benefit analysis in the second half of this year. You know, I think what, the way that you ought to think about that is, those would be 10 de novo patients, that do not include the patients that we've already, you know, sort of released data on. Those patients, that came from the ADVANCED-2 naive cohort will be beyond six month evaluable at that point. So we'll actually get a little bit of longer-term data. I think the full data set, we haven't put any sort of expectations out there, but I think 10 will be the minimum of patients that are, you know, kind of at a minimum six month evaluable. Because you remember, our primary endpoint is, is CR at any time, and so, Yeah ... those will all kinda count. We'll take a look at, you know, kind of where those patients are and their responses to 80 KE. And then, you know, we... I think we'll be able to tease out a little bit of information from our current dose escalation work, to sort of say, "Hey, look, is 80 so obviously better?" And we'll especially be looking at these concomitant Ta/T1 patients. You know, we'll be able to roll that over. I think when you think about the priming dose, it won't be, I don't think until after we hit our 25 patient futility analysis, sort of in the middle of- Okay ... next year. It'll be the point at which, you know, we would have generated enough information on priming, whether it was so profoundly impactful to results, you know, even more so than reinduction, let's say, that we would consider bringing that over into the ADVANCED-2 arm. And that one would, you know, require a protocol amendment. Okay, so if we understand this correctly, kind of the 80 KE potential higher dose could be implemented as early as later this year, potentially into your study, but the primary priming kind of option is- Mm-hmm ... might be a little bit delayed till next year. Just given the- Yeah ... the necessary kind of safety requirements of- Right ... IB, et cetera. Yeah. Okay. It's rate-limited by that animal work that'll be done by the end of the summer. Okay, animal work. Okay, understood. And, we didn't wanna gloss over the safety results for- Sure ... TARA-002, but Yeah ... obviously, we talked about all the different efficacy, but safety was something that our KOLs had commented on too. So do you wanna talk about kind of the reception that your kind of market? Yeah ... work has shown there? Yeah. So I think, you know, there is a general view that we share, and we hear it from KOLs, that, you know, everyone's gonna kind of be in the 50s and 60s, maybe the low 70s in terms of CR at six months. Even as recently as the AUA conference in early May, you're starting to hear about people say: "Well, I don't even really care about six or three months. I care about 12 months." So you're seeing that goalpost move, and you're seeing- Mm ... some of our competitors respond to that in the way that they're presenting data. But what we do here is... Look, I think as long as you are kind of in the frame from an efficacy stance, what then becomes a very important part of the adoption equation is safety and tolerability. And so far, TARA-002 has demonstrated that it is a, has a very favorable safety, and tolerability profile. I mean, the majority of our AEs are Grade 1, and you can kind of split them into two buckets. The first being, you know, AEs that are associated with the procedure itself. You know, and these are typical kind of urinary and bladder-associated AEs. And then the other series of AEs that we've experienced are flu-like symptoms or, you know, symptoms associated with a pro-inflammatory immune response. So it's almost sort of like a hint of efficacy or activity anyway. And so we hear that one of the real benefits, the, in the minds of KOLs, and these are especially, you know, kind of community docs, where the majority of- Yeah ... of NMIBC patients are treated, you know, very, very easy administration, you know, it's a quick reconstitution in saline, and then an injection. You're almost rate-limited by the speed at which a nurse can insert a Foley. So, the tolerability that I described, that safety that I described, as well as its sort of ease of administration, you know, has been the key point of excitement from many of the KOLs and investigators that we're working with. And I think as you think about TARA-002 as a commercial product, that will play very favorably into its TPP, if you will. And again, you know, 15 percentage points of CR in a study versus, you know, it's wherever we land, I think, you know, that we'll be in the frame, and as long as that's the case, then, you know, these other aspects of TARA-002 that are really attractive to KOLs will be, you know, determinants of adoption. Okay. Wonderful. And so we talked about a lot of different potential updates that you all are gonna provide in- Yes ... kind of the second half this year- Mm-hmm ... 2025. Do you wanna just walk through what data are we gonna see- Sure ... end of this year, next year? Just walk us through the different pieces that, that you might, that we should expect. Yeah. So, let me start with ADVANCED-2. Okay. So from ADVANCED-2, as I mentioned, we'll have a 10-patient risk-benefit analysis in the second half of the year. We'll likely tie that to a medical conference, if we can. And then, in sort of the middle, if you will, based on our current projections, in the middle of 2025, you'll get the sort of canonical 25-patient futility analysis where, you know, we've powered to exclude a 40% futility. I think 40%'s debatable at six months, but that's sort of the mechanics of the futility analysis. And then you could expect to see, around that same time, you know, results from an 80 KE cohort. Okay. You would also expect to see, in the second half of 2025, results from the priming cohort. We, we would like to be sort of right on top of that futility analysis for both of those options so that we're not kind of too far down the road in recruitment, if we need to kind of then, you know, change our administration. And then, you know, we, we also have announced plans to combine with a checkpoint inhibitor. The FDA has cleared us to go right into humans there, and, you know, we'll be getting that study off the ground this summer as well, and so you'd expect to see, you know, kind of the results of that, also in the second half of next year. Okay, wonderful. Lots of, lots of updates coming our way. And that's- Okay ... just NMIBC, right? So there's the other- Of course, yeah. ... programs as well, yeah. Exactly. Well, we'll focus on the oncology. Yeah. Exactly. Thanks, Stacy. The aspect of this is, we do know you have two other very interesting- Yeah ... programs that are kind of moving along. Okay. I'm gonna give you a chance to talk about just the broader, market landscape for NMIBC, where you think 002 fits in. You kind of alluded to kind of the range and efficacy- Yeah ... expectations that we should see, but just what- Mm-hmm ... just how does it, you know, we talked about the comparison, but just, it's an evolving competitive landscape. Mm-hmm. There's a lot of different players, and we still don't have a great sense of kind of guidelines, right? Right. For clinicians. So just, in the last few moments, walk through how we should think about TARA-002 versus some of these other updates. And just obviously compare that- Sure ... to what you're hearing from KOLs, in terms of opportunity. So I'll focus my response to that in kind of two different buckets. The first is timing. So right now, we're probably about 18 months behind some of the competitors out there, who will launch their products two very different kind of modalities. And sort of, if you will, pre-bake the market for us, as we follow them. And so, you know, if you think about time to recurrence for most unresponsive patients, that 18 months fits kind of nicely with kind of where we're seeing longer term efficacy from some of the competitive landscape. So docs, by the time we're coming out, will be looking for a differentiated alternative. And again, as the only modality that is a broad immunopotentiator, we would represent that to, you know, whatever is available at that 18-month time point. The other piece that I would say is, this is a, as we've talked about before, Stacy, it's a weird, immature, but very large oncology market. And if I look across the landscape of other oncology settings, they have all migrated to some version of combination. And I think as we learn more and more about the underlying histology behavior of the, you know, the NMIBC kind of tumor phenotypes and genotypes, then, you know, you'll probably see docs trying multiple different types of things. You're already seeing it, you know, in combination with checkpoints, with BCG, and I think that's why I just can't understand it would be weird if this oncology market didn't, as it matured, become like other oncology markets. And in that setting, we have no overlapping toxicities with any of the other agents out there. You could combine us with the pretzel, you could combine us with anything else that's out there. And that's a pretty good competitive spot to be in, as the world has spent 18 months sort of trying to figure out what they like and what they don't like, and what is replicating clinical data in real world, and what is not. Yep, the one last thing that our clinicians talk about is how desperate patients are to avoid cystectomy, so- Absolutely ... even as you kind of think about the marketplace, I think it should support multiple players, so. Yeah. Agreed. With that, thanks so much, Jesse, for taking the time to chat with us on Protara. Mm-hmm. Lots of catalysts coming up, so stay tuned, everyone. Okay. Thanks so much. Bye. Appreciate it.