All right. Hi, my name is Kelsey Goodwin. I'm one of the biotech analysts here at Guggenheim. I'm delighted to welcome the Protara team. Here with me, we have Jesse Shefferman, the CEO. So let's just start with some background on your lead program, TARA-002. You know, what exactly is it? Where did it come from? What's the history? Sure. Before I sort of describe 002, because it is a story. It originated in Japan in the 1970s, and was probably the first-ever utilized immuno-oncology agent, only nobody knew that. And that sort of kicks back to what is the underlying sort of philosophy or focus of Protara? You know, what makes us different from a lot of the other small mid-cap companies out there in oncology? And I would say it's the way that we go about building a portfolio of assets and how we have historically built our portfolio of assets. Our focus is on essentially trying to find the next Revlimid, right? Thalidomide in the 1960s, we know all the stories about thalidomide. It became a $6 billion oncology product after someone sort of recharacterized how it might be utilized in a different patient population, and that's what we're looking to do with our strategy. Where are there opportunities, mostly through new biology- Mm-hmm. Right? New understanding, new assays, that type of stuff, new science, but could also be new regulatory paths, or it could be new manufacturing opportunities in established mechanisms, where you sort of have a level of de-risking as a result of its historical use. And that's what 002 is. Mm-hmm. So, 002 is an inactivated strain of Streptococcus pyogenes that was immortalized in the 1960s by the University of Kanazawa in Japan. And what that means is that where the genetic drift on that particular pathogen, that eukaryote, I'm sorry, prokaryote, got that wrong, was immortalized at that time, means that, that's that genetics, those, the profile of that particular bug will never change. And we now have equal access to the master cell bank, along with our Japanese partner, Chugai Pharmaceuticals. So why is this something that you might utilize therapeutically? Well, in the world of immunology, if you take a pathogen whose relationship with the human species is incredibly well conserved over, you know, millennia, you've developed point, counterpoint, point, counterpoint between the human and the pathogen that drives a pretty substantial immune response. Except for that through our manufacturing process, we have engineered out the streptolysin toxicity so that the body recognizes the antigen, drives the immune system into overdrive, but there is no underlying toxicity that you might get with sort of attenuated bacterial therapeutics. Right now, of course, the most commonly utilized bacterial therapeutic is the BCG vaccine. Mm-hmm. In NMIBC, which is where we are developing 002 as an alternative to BCG, and perhaps even something that you would utilize after BCG is no longer working for patients. Great. That's perfect. So I guess building upon the NMIBC, I guess maybe walk us through the opportunity there and how the current treatment paradigm works, and- and the treatment options there. Sure. So I'm sure most of the folks in the room are aware of a sort of emergence of enthusiasm and excitement around NMIBC. I'll just talk through some of the epidemiology, and then maybe we can talk about where and how we think about the NMIBC market. So, you know, if you're familiar with NMIBC, you know that there are about 85,000 cases of muscle, I'm sorry, of bladder cancer annually. Of those, about 65,000 are new incident cases of NMIBC, and approximately half of those would fall into the high risk, high grade sort of category, where it's either by histology or by focality or size of tumor, you would characterize those as being of a higher risk. So think about your sort of new emergent cases in the 30,000-40,000. Mm-hmm. -range, right? What we know just from broad epidemiology, it's the sixth most prevalent cancer in the United States, fourth most among men. That's a really, really big oncology indication. Punchline that I'll jump to is, it's only been in the last two years that new products have been sort of interrogated or under development. That blows my mind. T hat something so large in terms of an oncology indication would not be the subject of significant new drug development, and luckily- Mm-hmm. We are a part of what that would be. Mm-hmm. You asked about sort of where the opportunity is? Mm-hmm. Mm-hmm. Yeah. So I talked about the new incidence cases, right? 30,000, that's a big oncology indication, you know, on its own. But what is interesting about NMIBC for the uninitiated is that while it is not particularly mortal, you know, you can't count on it to metastasize or even advance locally, but it is incredibly recurrent. Mm-hmm. So, you know, depending on where you're drawing your numbers from, you should expect a, you know, a five-year recurrence rate at about 80%. Some folks would say it's a three-year recurrence rate, is about 80%. So if you think about it, it's not super mortal- Mm. But it can be really bad if it goes locally advanced or metastatic, right? And you really only have a handful of generics and new investigational products able to treat the, you know, the disease if it recurs. And then soon after that, guidelines would say, "You are scheduled for radical cystectomy." Right now, that is a highly, highly morbid outcome. Mm-hmm. -for a lot of patients. And so when we talk about what do we think non-muscle invasive bladder could be, I often talk about it in terms of, ulcerative colitis or inflammatory- -inflammatory bowel disease. In the early 1990s, you had 5-aminosalicylate acids, you had steroids, you had some emerging antibodies. But if you think about that, highly indolent disease that is recurring constantly with very few options for treatment, ultimately resulting in bowel resection.... So we're sort of talking about similar dynamics, smaller epi on the bladder side, admittedly. But that's where we think, you know, NMIBC is headed first, second, third, fourth, fifth, sixth, seventh, eighth line therapy. Mm-hmm. You've got an epidemiology, especially with that recurrence rate, that supports, you know, significant numbers of players, significant numbers of modalities, combinations. I think it's a wide, wildly immature oncology market that is about to get very mature. Mm-hmm, mm-hmm. Yeah, that's great. So you have an ongoing phase I and phase II trial, maybe. Let's start with the phase I. What was the design? What data's been presented? Yeah. What are we going to get? Sure. So we have completed a phase Ia dose-escalation study. For those of you that have some familiarity with 002, its predecessor compound that was utilized commercially in the oncology setting in Japan for many years, we basically have a lot to look back on in terms of- Mm-hmm ... its, you know, patient experience and its safety database. In fact, the safety database of our sister compound, OK-432, is about 65,000 patients. But, and this has been administered in every type of administration function you can possibly imagine: oral- Mm-hmm ... subcu, systemic. But it was never administered intravesically- Mm ... for regulatory purposes for the bladder. So, we had to do a 3+3 design that was sanctioned by FDA. We were hoping to get some CIS patients in there. Obviously, the epidemiology is tough there. Mm-hmm. So we did a 3+3 dose-escalation. I can tell you that our max dose, we did not hit an MTD, but our RP2D is 8x that, that was utilized historically in Japan systemically. So you can see that, you know, as in the bladder, with a very closed system, you can really push dose. Mm-hmm. We were lucky in that 3+3 design, total of nine patients, to enroll three CIS patients. Mm-hmm. What we would have disclosed publicly there is we had a complete response in a heavily pretreated BCG-refractory or BCG-unresponsive patient at half our RP2D. Mm. And then at our RP2D of 40 KE, KE is just a German phrase, klinische Einheit, clinical unit. Mm-hmm ... number of cells in a vial. It's really hard to quantify, you know- Mm-hmm ... when your API is a, you know, inactivated bacteria. So, 40 KE is our RP2D, and at that dose, we had a naive patient that had CIS, that had significant tumor regression, very heavy disease burden at baseline, and after only an induction course, and this is important that we talk about induction- Mm-hmm ... plus reinduction. Mm-hmm. After an induction course, that patient had no visible disease at baseline, and was only deemed a non-response via cytology, right? So we're talking about right up to the finish line on a naïve patient, and we're looking at the differences that could potentially exist between a naïve patient or a BCG-experienced patient that might have some level of trained immunity hanging around that can amplify. And we're sort of- Mm ... moving forward into the phase II. We have gotten sign-off from FDA on the standard, BCG-unresponsive CIS open-label study for traditional approval that every other one of our competitors is out there doing. And so that, that's where we're actually looking. I think when we first started talking about Protara and the value proposition, it was, "Hey, maybe we can be a replacement for BCG. It's always in shortage," et cetera, et cetera. But as we have developed data, and certainly if you look at the data we presented from the phase Ia, it's clear that we are having a response in BCG refractory patients. And as you know from the 2018 guidance, that's your fastest path to registration, but it's certainly not the only opportunity in NMIBC. Mm-hmm. Got it. So maybe just walk us through kind of where the phase I stands now and when we'll get the next data set there. Yes. So, while we were doing our phase Ia dose escalation, where we were just, you know, dosing patients via induction out to three months for follow-up, it became clear to us that, in the academic setting, and there's a big kind of divide between the academic and the, community settings for non-muscle invasive cancer, non-muscle invasive bladder cancer. You really need the academics to drive sort of adoption, if you will- Mm ... and interest and clinical validation, but the majority of your commercial product is gonna be administered in the community. Mm-hmm. 80% of all intravesical installations of either chemotherapeutics or BCG are administered in the community setting. These folks matter. However, you do want to bring along the academics for all the reasons that everyone in this room can understand. And I don't know if any of your other companies that are in oncology have articulated this to you, but for whatever reason, over the last two years, IRB processes- Mm ... in the academic setting are massively slowed down. They may not like it, but I'm gonna say it took us 15 months to get through the IRB at Mayo. Mm. So how do you, if you've now achieved your sort of RP2D, and we rolled immediately into having a dialogue with FDA about our registrational BCG unresponsive arm, or study that we believe continues to be sufficient for registration based on FDA feedback. How do you continue to get these thought-leading academics to have experience and comfort with your drug while they're getting through IRB over more than a year? Mm-hmm. So what we do is we added an expansion arm, what we're calling ADVANCED-1EXP, that basically is CIS only, all comers in terms of BCG experience. So that could be anything from refractory to naive to this new sort of inadequate treated, you know. That's there so that those academics can continue to gain experience with our drug, and that'll be the first data set that we talk about publicly since we talked about our 3+3 dose-escalation study. I will highlight that because we wanted to get that extension study, we say it's about 12 patients, we wanted to get that in as quickly as possible. It would have taken another protocol amendment to really follow these patients past three months. Mm-hmm. This ADVANCED-1EXP, I guess, is of the phase I you could think about as the absolute floor of efficacy when we report it out. We'll probably be able to report out sort of stratification of unresponses versus inadequates versus naïve. And we've guided that we're gonna put that interim data analysis of EXP out in the first half of this year, and we're still on track for that. Okay, great. And maybe just roughly number of patients there? In EXP? Yep. Yeah. So that's 12. Mm-hmm. What's interesting is I talked about that study is a function of academic sites being able to roll on to the new registrational IRB. Mm-hmm. So the idea is, you know, we might do a couple of patients fewer than 12, we might do a couple of patients more than 12. It's a function- -of just continuing to allow the academics out there to gain experience with the drug. Well, meanwhile, our ADVANCED-2 program, which is 75-90 patients, single- arm, open-label study, CIS, BCG-unresponsive. Again, this is the study that everybody else is doing. Mm-hmm. That study, we enrolled our first patient there in September of last year. Mm-hmm. What's interesting about that study is we've got a second cohort under that protocol that we call sort of Cohort A, which right now is 27 patients, BCG naive. Mm-hmm. Here, what's important about the ADVANCED-2 study is that we will allow for reinduction and maintenance out to two years. Mm. What we've observed biologically about 002 is that it's an incredibly well-tolerated product. We know this from the Japanese experience, and we know it from physicians that are reporting back to us. So you can think about its onset of action as being sort of like this. Mm-hmm. We believe that if you provide for a second round of induction at three months for non- or partial responders, you're gonna be able to pick up a significant salvage rate- Mm-hmm. At six months, and that's what matters 'cause our primary endpoint is CR at any time, up to six months. Got it. I guess specifically in this BCG unresponsive setting where, you know, a lot of the competition is addressing first- Because of this kind of like loophole with the FDA in their guidance. Right. I guess maybe just walk us through the efficacy bar and where, you know? Mm-hmm. What is a win in this setting? It's a great question. I don't think we really know. Mm-hmm. I tend to just directly engage some of the KOLs that we've built great relationships with and ask the same question: Where do we need to be to be a well-adopted product? Mm-hmm. I'm just gonna try. I know we're gonna be, I'm gonna push on time here, but here's what you have right now in the unresponsive setting. Over here, you've got what I would call enhanced dwell time chemotherapeutics, direct cytotoxics. This is TAR-200, this is UroGen's product, if they ever take it into high grade, you know, high risk. Over on this side, you've got what I would call targeted immunotherapy and targeted immunotherapy combinations, right? This is your CG Oncology, ImmunityBio, it's the checkpoint inhibitors. If you think about it, again, activating very specific cytokines or chemokines, and, you know, what that tends to drive is an immediate big response, right? 'Cause your innate and adaptive- systems go, "What the heck?" Right? You're really pushing on one cytokine or chemokine really hard. In the middle, you have broad-spectrum immunopotentiators, TARA-002 and BCG. Mm-hmm. The idea there is you are hitting all of these different cytokines. There are at least 10 different cytokines and chemokines that we activate, some that overlap with BCG, some that don't. And in my mind, I go back to this idea that there's this well-conserved back and forth between these two fairly ancient- Mm. You know, species, where if you're only attacking on one front, you might develop resistance. The body tends to do that. But if, as with a broad-spectrum immunopotentiator, if you're hitting IL-12, if you're hitting IFN-gamma, TNF-alpha, GM-CSF, we activate all of those. It's sort of a way to point counterpoint and continue to keep that immune response happening, but most importantly, you are very rapidly recruiting CD8-positive T cells to come in and do what they do cytotoxically into tumor cells. So I didn't answer your question, what's a win? But I'm kinda laying out for you what the spectrum looks like. Let me tell you what I think is sitting here at a negative enterprise value when one of our competitors just got valued at $2 billion. Let me tell you what I think is, is interesting. I think if at three months, we could produce data that is sort of in the 60-ish to like low 60s at three months, because you know you got another bite of the apple with reinduction. Mm-hmm. Right? So to me, a home run would be being in the 60s at three. If you look at all other immunopotentiators, including BCG or other immune-activating agents like durvalumab in the POTOMAC study, or Immunity Bio, or even CG Oncology in its most recent study, there's a 30%-50% salvage rate for CRs when you reinduce or rechallenge sort of partial or non-responders at three months. There's no reason biologically that we wouldn't expect something similar for ourselves. Mm-hmm. Right? So if I'm at 60 at three and I can salvage half-... I'm probably best in class. Mm-hmm. So let's say what's like, what's good? What's like a good product that's gonna get utilized? I think you can look at Adstiladrin right now that was approved recently from Ferring. 50% complete response at three months, I'm sorry, at six months, and a duration of response of nine point seven months. So not super durable, but 50% complete response and unresponsive, right? That's threee patients out of 10 incrementally that are not going on to cystectomy. Mm-hmm. I think 50% at three months, even, let's say we have, like, a 25% salvage rate, that still puts you into a category where we've heard over and over again from docs, you will get utilized all over the place. A, in the combo setting- Mm. - because we do not have overlapping toxicity with any of the competitors that I've listed. Or just as monotherapy for particularly frail or fragile, you know, elderly patients who comprise a fair amount of non-muscle invasive bladder. Mm-hmm. And then, you know, what would we say, "Game over, it's time to, you know, take our ball and go home? I think if at three months, you know, we were sub 30%, then I think it's time to say, you know, even a 100% salvage rate- ... would get you to utilizable, but tough. Mm-hmm. Mm-hmm. Got it. We, you know, we'd have to see where the world is competitively at that point. Remember, no one has gone to the FDA with a BLA and not gotten a CRL in this space. Everyone has. Mm-hmm. When people talk about the competitive landscape, I have to say, and it's not a great answer, I think, for most investors, they say, "Let's wait and see. Mm-hmm. Let's wait and see." We know how rigorous the FDA is on, inclusion, exclusion, and baseline characteristics at, for the unresponsive setting. It's almost sort of like, "Great, we're gonna give you the single- arm study design, but man, your Ns and Xs better be right on the money. Yeah. It's really hard for some of these treatment-experienced patients to say, "Okay, I'm gonna confirm adequate previous BCG usage." We know that some of our competitors that have had CRLs got tripped up on exactly that. Yeah, yeah. Got it. So maybe that's a great kind of overview also of the, of the competitive landscape. I guess maybe thinking and going back to your earlier point of, you know, just how big this opportunity could potentially be- Sure. Maybe just, like, help us quantify, if possible, or just better understand, you know, like, if we're working with this massive market, we have this high recurrence rate. Yeah ... and now we're bringing in all of these agents that have some benefit and, you know, maybe comparable benefit- ... maybe, you know, how do we even kind of model out the opportunity once we bring in this prevalent pool and cycle patients through? Yeah, yeah. So one of the things that I have talked about, and this is, by the way, what you just, it's a 750,000 patient prevalence population. Mm-hmm. That's the NIH's number. That's not something that somebody made up. That's right out of the NIH, right? So if you are assuming that, you know, the epi within that population follows that of newly incident cases, then let's say that 30%-40% or 50% of that are these high-risk, high-grade kind of patients who are more likely to recur. Mm-hmm. Right? So let's give ourselves credit for 30%-50% of that, and then say, you know, there's a 0.2% chance if you're gonna say that there's an 80% recurrence rate at five years, that they will recur. So it's like 0.2 x 0.3 x 750,000. I can't do the number in my head, but that, I can assure you, is not a small number. Yeah. Right now, in that unresponsive setting, you've got two drugs that are approved: KEYTRUDA, which is durable, right? It doesn't help everybody, but when it does, it's about a 20%, 12-month non-recurrence rate- Mm ... or a complete response rate. And then you've got Adstiladrin, that's 50%. Mm. Right now, let's just say you need to know that your patient is disease-free at 12 months to sort of call it a win, right? Otherwise, you are gonna be indicated to move on to either a clinical study or cystectomy. That's the guidelines from AUA. Mm-hmm. All right? So let's imagine that that holds true. We know from claims data that patients will try six or seven different things before they go on to cystectomy. But let me take you back to this number. Whatever that number was, 0.3 x 0.2 x- Mm ... point, you know, 750,000. When those patients recur, let's just assume that everybody gets approved, right? CG, enGene, Protara, TAR-200, everybody gets approved, and the aggregate response rate within the unresponsive setting moves from 0.2% or point, you know, two out of 10 with KEYTRUDA to seven out of 10. Let's believe everybody's 70% numbers. Mm-hmm. Right? So if I go from eight out of 10 patients by guidelines would be destined for cystectomy, now it's only three out of 10 patients that would, through guidelines, be sort of destined to move on to cystectomy. They're either bladder crippled or something- Mm-hmm ... you know, along those lines. I've now increased the number of patients that are surviving and staying in the prevalence pool by 50%. Mm-hmm. I'm adding five patients out of 10 into the prevalence population, and what we know is that nothing on the market to date cures this, but it does treat it. Those patients will recur. And it's a very morbid way to look at it, but what would you say the NPV is of five incremental patients out of 10 in a 750,000 prevalence population, staying in the prevalence population and not exiting the prevalence population? Mm-hmm. So when you hear folks like, you know, some of our competitors out there saying this is a $5billion, $6 billion, $7 billion aggregate opportunity, that's absolutely right. Mm-hmm. I think it's actually probably bigger. Mm-hmm. Put a 4x revenue multiple on a $7 billion opportunity. Mm-hmm. There's enough room for a lot of folks to see their valuation come up, and hopefully, we will be among that mix, and we make the case for that with data- Yeah ... this year and into the next year. Yeah, got it. Okay, I know we're running tight on time, so maybe just so we'll get this phase one in the first half, maybe just confirm for us- Yeah, I'll talk very quickly. Move on to phase II. Yeah, so very quickly. In the first half of this year, you're gonna hear data out of ADVANCED-1EX. Mm-hmm. That's gonna be, again, our floor level of activity, and it's gonna be descriptive of both BCG unresponsive and BCG-naive and experienced patients. In the second half of the year, we have a first pre-specified interim data analysis on the single-arm open label study. That will be approximately 10 patients. All of them will be post- reinduction. The idea is this: where are we confirming our suspicions around what reinduction can offer for partial or nons? And then the canonical sort of next piece of data would be probably in the first half of 2025. Mm-hmm. That's a 25-patient futility analysis, all BCG unresponsive, all post-six-month evaluation. Okay, perfect. I know we're wrapping up on time, but just one quick one, lymphatic malformation. Potential option, Yeah ... or you know, there's maybe a path there to getting a priority review voucher, maybe just a quick- Sure. So we've gotten our- 36-second pitch. Yeah, we've gotten our PDD. This is the standard of care in Japan. There have been tens of thousands of patients treated with this around the world. There are 2,000 incident cases per year in the United States. There's no approved product, and we are basically following the same study protocol that got the product approved in Japan and was utilized by the University of Iowa in 550 patients via compassionate use. Mm-hmm. Effect size was 86% complete or substantial response for these kids, and we are enrolling, and we'll have updates sort of in the second half of the year, kind of middle of the year, on where we are with lymphatic malformations. Perfect. The final question that you're gonna ask me is about our cash balance. We are at about $60 million, and that carries us well into 2025. Perfect. All right, and with that, we will wrap it up. Thank you so much, Jesse. Thank you. This was really great. Thanks.