Good morning. Thanks, everyone, for joining our 45th Annual Healthcare Conference. I'm Stacy Ku, part of the biotech team. I'm here with my colleague, Vish Shah. We'd like to welcome Jesse Shefferman, CEO and founder of Protara. Thanks so much for joining. Also, thanks to Jackie, Patrick, and Justine that are part of Protara, key to Protara, and in the audience. We're getting a lot of investor interest in the NMIBC, and we're really excited to be discussing TARA-002 today.
Thank you.
Just quick introduction, some background on TARA-002. I do think awareness is slowly increasing, but just as a reminder, talk about the mechanism of action, why it's de-risked, which is unique in this current trading environment, and maybe how you guys got the product in the first place.
Yeah, so we could probably take the whole half hour talking about the background of 002. 002 is a genetically distinct strain of Streptococcus pyogenes that was originally developed as a pharmaceutical product by Chugai Pharmaceuticals in Japan in the 1970s. Like BCG, the Strep pyogenes that underpins this therapeutic is a broad immunopotentiator, meaning it's sort of a well-conserved point counterpoint where the pathogen has multiple modes of attack, and the human body, in response, has multiple modes of response. You're activating the innate and the adaptive immune system. It's a classic Th1-type pro-inflammatory response. To just round out, what is unique here is 002, through a lot of the nonclinical work that we've done, we've discovered that 002 is a downregulator of IL-8. Why is that important?
So IL-8 is associated with prompting recurrence of most of the phenotypes of non-muscle invasive bladder tumors. In fact, BCG, as a TLR4 activator, upregulates IL-8. In some respects, it works against itself. When we get the question, how are you different? We're a lot alike, but where we're really different is we are knocking back the signal that drives a lot of recurrence. Just to round it out, of course, this was a drug that was once one of the largest selling oncology products in Japan. Like as often happens, sort of was lost to history. Before that happened, the safety database of its utilization in Japan is up to about 250,000 patients. To this day, there are approvals for its adjunctive use with chemotherapy in lung, gastric, and head, neck, and thyroid cancers. That's sort of the cool background.
Of course, a lot of the theoretical discussion has kind of translated into some of the clinical data that you've shown so far. Very early days, of course, but maybe discuss some of the exciting data you've disclosed.
Yeah, so we've put out two data releases. I think kind of most recent is sort of the most important. Back in May of last year, we put out three-month data in about 16 patients across BCG exposures. Our objective with that data set was to really articulate that this was an active drug. We had not yet demonstrated what exactly the activity was of 002 in the NMIBC setting. We feel like we demonstrated that. At the same time, those numbers that we produced at that time were not competitive. We asked investors to stick with us because what we learned about the mechanism of this drug is that its kinetics are slow to onset.
Before you are out there recruiting CD8 positive T cells, it can take some time because of that point counterpoint between the human body and the pathogen that's pretty well conserved over millennia. Fast forward to December of this past year at SUO, we put data out on 20 patients, of which 15 were BCG naive patients. It's the first BCG naive data that has been published by a sponsor, and five evaluable BCG unresponsive patients. We, at the time, sort of pooled the data across BCG exposures because that just sort of helped us articulate how these dynamics are working. What I'll say is, in the BCG unresponsive patients, small N, we were at an 80% complete response rate at any time and 100% complete response rate at six months as a landmark with an 83% reinduction salvage rate.
That thesis that we had of, hey, there's a slow onset to peak therapeutic effect, but keep dosing these patients. If you're not quite at CR at three months, hit them with another induction dose or around. That proved to be the right answer. Across the unresponsive patients, small N, there were CIS-only patients, so no concomitant papillary to sort of decrement the overall response. That's obviously a number that we think will come in, but it's a great starting point. Just very quickly, in the BCG naive setting, where really what you're looking to do is be in the neighborhood of BCG, we demonstrated a 72% complete response rate at any time and a 70% complete response rate at six months. That's right on top of, if not better than, many of the studies with BCG.
It argues that there's a there there. We can leave that for now. As you take a step back, whether it's a naive patient or an unresponsive patient, we believe that the data that we put out in December sort of articulates that this drug works in NMIBC.
Of course. That's wonderful. You covered everything in great detail. I appreciate that. It's all in your head. Obviously, as we think about maybe the broader, let's say, a greater number of patients in the BCG naive patients, that's obviously something, a data point that others have not necessarily shown, still very much within the range of what KOLs tell us is BCG, which is 50% to 70%. Obviously, a lot of different ways to interpret the data. You have caveated all the different background therapies. We might argue that within the BCG naive population, there were far more concomitant papillary disease patients.
That's right. Yeah.
OK. Perfect. Let's talk about that salvage rate that you kind of brought up. Obviously, 80%, around 80% today. But e ven if it goes back to the 50% range, that's still very competitive. Just maybe talk through your expectations there.
Yeah, so I think actually you've articulated our expectations. I think the question that we get, and we don't shy away from it, is what are your numbers that are apples to apples to CG to NGen to J&J to Adstiladrin? And those numbers are small, but growing. One of the things that we talked about in December when we raised capital on the back of that data was, what are you going to use this for? The first bucket is to sort of accelerate enrollment in the BCG unresponsive setting. I can tell you just raw numbers. The data that we presented in December was derived from seven sites in the United States. If you want to enroll BCG unresponsive patients, you have to get into the academic setting, and you have to get international.
Today, we have about 28 sites up and running, and that should be up to 30 by the end of March. That should tell you kind of where that enrollment is going to come from. From our perspective, the story for us at the moment is get those patients enrolled. Of course, what is the 12-month data going to be?
OK, wonderful. Remind us, are you part of the SUO Consortium for Patient Enrollment?
We are. The SUO CTC, yeah.
OK, understand. You talked about the 12-month data. Maybe set some expectations for the mid-year results as we expect them.
I think, look, people want to know what's the number, and people want to know how many patients. I can go to our publicly disclosed information to kind of help everybody tease out where that second answer is. If you look at the swimmers plot that is in our corporate deck today, you'll note that at that time, remember the data cutoff was November 19 of 2024, we had 11 patients across BCG exposures who were on a protocol that allowed for continued dosing past the six-month time point out to what is the 24-month end of study.
If you look at the swimmers plot of the six-month patients and nine-month patients that were still in CR and on the appropriate protocol, you would be able to tease out that there were a max of 11 patients who, six months after November 19, would be included at least in the denominator of the 12-month evaluable patients. What we've said is the maximum number of 12-month evaluable patients across BCG exposures that we will be able to talk about by mid-year is about 11. We've also added nine, six, and three-month patients to that overall N as well.
OK, wonderful. I think that's pretty helpful. Sounds like we're going to get some additional patients that are three and six months. Obviously, we'll all be looking to the 12-month data.
I think one of the things that we'll be able to do as we enter the second half of the year is begin to show swimmers plots and data sets on a standalone basis, naives and unresponsives.
OK, understood. You talked about enrollment of the BCG unresponsive patients, key fertility analysis of these patients, 25 patients, I believe, will be your year end. Based on the very early data we have so far, what kind of expectations do you all internally have? Maybe overlay that with some of the evolving KOL perspectives.
My internal expectations are brutal. Our Clin Ops folks, they work their asses off. Here's what we've today: we put out, I believe we've got a press release out today where effectively we've reaffirmed all of our timing guidance. Think about it, Stacy, that timing guidance is informed by what we have learned since November. We're in March now. Time flies. Two key important reaffirmations of timing are that we continue to stand by our guidance that we will put out an interim sort of analysis towards the end of the year of BCG unresponsive only patients, targeting 25 enrolled patients that would be six months evaluable at that time point. We are also reaffirming our guidance that we expect the unresponsive arm of ADVANCED-2 to be fully enrolled by the spring of 2026.
OK, wonderful. I'm sure this is something you and Jackie could talk about again for half an hour. What if you could.
Jackie and I can talk about anything for half an hour.
At least for.
For our purposes.
Within the BCG unresponsive population, how are you thinking about the patient split when it comes to enrolling patients, making sure you have enough, but thinking about the split of CIS only patients and concomitant CIS papillary patients? What are you seeing in other studies? Are you guiding towards any type of expectations for your own analysis?
Yeah, so look, sometimes being a fast follower is a good spot to be in. As we look at the enrollment characteristics of either approved products, so in the registrational studies of approved products, or in studies of investigational products that have made it through sort of that registrational study, we look at the enrollment characteristics. You have very early on, Stacy, caught on to what we think is sort of the big elephant, which is concomitant papillary patients with CIS are just harder to treat. It's been some time since other sponsors in the space have sort of published response rates broken down by CIS versus CIS plus papillary. What we saw in our data set where we had that split, which is in the naives, we demonstrated a 90% plus or an 80% percent. I'm embarrassed. I don't know this number off the top of my head.
A really high response rate in CIS only patients and about a 50% response rate in concomitant papillary. 50% is medically meaningful for a harder to treat patient. We would like to see that number get better. We would be very happy if we can stay in sort of the 80s or 90s for CIS only. Why do you enroll concomitant papillary patients with an immune agent if you know that they're going to perform worse than your CIS? Wouldn't you rather do CIS only and have like an 88% complete response rate? The answer is it's difficult to tackle the largest patient population in NMIBC, which is papillary only. We know that the FDA back in 2020, when we talked with them about papillary only, wanted to see a sort of a comparator with a stratified investigator's choice with a 24-month complete response rate endpoint.
It's tough. As long as you've got a representative sample within your CIS population of CIS plus papillary, what we've observed is that sweet spot's about 75% CIS, 25% concomitant. That's going to get you on NCCN guidelines for papillary because you demonstrated safety and efficacy in a papillary sort of adjacent or a papillary affected patient population.
OK, so we'll get to kind of the first line questions that we'd get from some investors.
Let's do it.
Before we do that, let's talk about the market because that is actually where we spend the vast majority of our time as investors trying to understand the prevalent market for BCG unresponsive patients. As obviously, most look at it from an incidence population, but many of these patients kind of stay within different types of treatment over the course of a few years. Yeah, so how many patients, in your view, maybe walk through your analysis as you think about your prevalent population and target market?
Yeah, I want to caveat that what I'm about to say is not scripture because there's a big sort of variable in the algorithm that we can debate forever. Let's just start with what we know is the prevalent population.
Actually, before you start, I will say that there is a range that other companies have put forward around 60,000-145,000. With that kind of as backdrop.
Oh, let's start with that. We think that there are roughly 65,000 to 70,000 high-risk, high-grade patients seeking treatment in the U.S. in any given year. That is comprised of both newly incident, and that means sort of BCG naive. They might have been treated with chemos, but that's a newly emergent case of NMIBC and a cohort of patients from the prevalence population that have now recurred back into the seeking treatment category. We think it's about 65,000 to 70,000 in the U.S.
OK, wonderful.
That was easier than I—you heard me tee up some math there in your.
Yeah, I saw you ready to do that.
Thank you for preventing me from doing that.
As we think about maybe one point that we wanted to make sure we touched on is the treating clinician that's unique for bladder cancer. Obviously, urologists, their focus is a little bit different from a medical oncologist. When we talk to them about TARA-002, they really emphasize the safety and administration aspects. Maybe walk through your value proposition for TARA-002 versus maybe some of the other agents that are out there in development.
Yeah, so I think at the end of the day, you're right. You're all GU oncologists because we are in both prostate and in non-muscle invasive, which are sort of their two biggest disease states that they treat. In general, these are not highly mortal cancers. We're looking to prevent recurrence. We're looking to prevent sort of progression. That makes NMIBC and prostate together, and I'll stop lumping in prostate because it quickly becomes its own thing. It makes it look more like an indolent chronic disease that is highly recurrent but not necessarily mortal. When you reach the end of the road, you're looking at a major organ removal. It's, again, very much like ulcerative colitis. You have to think about where these patients are being treated.
First of all, it's dangerous to overgeneralize, but we've always known that there's a big community setting and a big academic setting. The community settings are, by definition, people who have moved out of the academic setting. With a broad brush, you can paint them as being more economically sensitive. There, it's procedure-based. How long is the patient on the table? Do I need to be in the room, or can a nurse be in the room? How long is the prep? When the patient leaves my office, what am I handing them? How many sheets of paper am I handing them that talk about post-administration sort of follow-up in that? Let's not fool ourselves. It's cancer. High response rates equals high adoption. That will always be the case.
I think what we're seeing is relevance at the six-month time point, probably need to have like a six or a high five. Great if you have a seven in front of your number. At 12, 30, you'll get adopted. 50, you're competing with the best out there. I'm sorry, 40, 30, you'll get adopted. 40, you're competing. 50, you're best in class. That has not been settled yet, that 12-month response rate. Let's assume that everybody is through these thresholds of relevance from an efficacy perspective. The things that you mentioned matter. We're a 15-minute start to finish administration, no thaw time. Nurse can do it via Foley catheter. There's no cytoscope. Importantly, relative to BCG, which is what they all anchor on, what is my post-administration protocol?
For BCG or for some of the other sort of live pathogenic vector type things, I'm not naming names, you've got to stick around for a while to ensure that you aren't undergoing some broader systemic infection. Because 002 is inactivated, we don't ever worry about that. We can point to 250,000 patients in Japan that have never gotten sepsis via systemic administration. Think about this. Not a lot of people talk about it, but when you take BCG or some of these other kind of viral vectored agents, you've got to go home and bleach your urine. You've got to go home and use a different toilet than the rest of your family. You've got to watch for signs of sepsis. None of that with 002. You don't even have to do the rolling back and forth on the table that people talk about.
Just from start to finish, the administration dynamic and the follow-up dynamic of this particular treatment is really compelling to these guys that are out there looking to drive procedures through their practice.
OK, as we think about multiple agents that are in development and obviously no guidelines, clinicians do have to kind of make a little bit of a judgment call. Cystectomy is obviously a clear choice for some. Yesterday, our bladder panelist mentioned that the national range is 10%-20%. He's an academic and a surgeon, so he is closer to 40%-50%. Just help us understand maybe those different types of dynamics as it relates to the introduction of multiple agents.
Yeah, so I'm going to try and, with atypical brevity, try and address sort of three different things that when you ask me that question, they kind of pop into my mind. First is, what are the patients that we are treating today? What's their background? I can tell you that right now, we have multiple patients who are in CR after being treated with TARA-002 that failed not only BCG, but gemcitabine, Keytruda, and actually a recently approved product that is available in the BCG unresponsive setting. As I look at that, that's a patient that opted for six rounds of treatment and then went for a seventh, I think if my number's right, to get TARA-002. There are so many facets and factors that work into the dynamic of cystectomy or not.
We're starting to get questions of like, really, I only give two rounds of treatment to my patients, and then I go to cystectomy. When I hear any physician utilizing that type of language, I wonder, frankly, is this a chair of a department? Is this someone that has been practicing for 30 or 40 years? Because with no disrespect, what we have seen, and Jackie has really pinpointed this, there is a sort of a bifurcation in GU oncology between sort of a category of rising stars and sort of old dogs. If you go on Guidepoint and you ask to talk to a specialist, you might get—I'm not going to name the name—but you'll get someone that's been around for 40 years. It's a surgeon who's prolific on Guidepoint.
Success and sort of accolades for that person when they were coming up as a young surgeon was the ability to perform an open surgery, removing an organ and creating a neobladder so that that patient didn't die. Fast forward now, you've got a whole cohort of these uro-oncologists that we really connect with that are sort of five years away from being department chairs. When you talk to them, they say there are two words that we want to remove from our vocabulary. I am thinking about a specific one who's recently become the head of all clinical research in GU oncology at NYU Langone. She says, there's two words that I want to remove from my vocabulary: cystectomy and BCG.
Again, when you wear a hammer and everything's a nail, if the greatest medical achievement you've ever performed were multiple open organ removals and the patient survived afterwards, you're tuned to that. But there's this increasingly more prevalent patient, a physician who never wants to do another cystectomy.
Yep, of course, the median age of these patients tend to be elderly. Of course, that's important in the calculation of whether or not you want to impact their quality of life with a cystectomy versus maybe a younger patient that.
It's paradoxical, right?
That they do want to maybe think about more aggressive options.
If I'm 36 years old and I have CIS plus TA, and it's been only three months since my last recurrence, and I've got three kids, I'm going for a cystectomy. That is a massive outlier compared to what we know, which is that the average age of diagnosis of NMIBC is about 72 years old. You go through a few rounds of treatment, you're into your 80s, you're like, yeah, you know what? I made it this far. Let's try something else.
OK, obviously, we're going to be watching the evolving space of the market for these patients. I think right now, some views are that it's a billion, but clearly a little bit larger. For us, we can get to $500 million on 5% penetration of the prevalent BCG unresponsive population. In the last few moments, obviously, very briefly, let's talk about potential additional plans for TARA-002 and bladder. It would be remiss for us to not at least have you talk about the broad pipeline behind the scenes.
The rare disease portfolio, yeah.
We run out of time every single time.
It's because I talk so much about hopefully something enlightening. Anyway, look, the other buckets, if you will, within NMIBC beyond BCG unresponsive, CIS with or without papillary are high-risk, high-grade, naive patients, low-grade, intermediate risk, or just intermediate risk, however you want to define it, and then sort of broadly the high-risk, high-grade papillary. High-risk, high-grade papillary is a several thousand patient study. I don't think you'll see any individual kind of standalone sponsors or independent sponsors go after that. We've generated data that says there's a there there in the BCG naive setting. It's down to what does the FDA want to see us run as a comparator in an RCT because you have to go RCT in the naive setting. What we've stated to the street is that we're going to the FDA in the first half of this year to get guidance.
We're going to propose a gemcitabine monotherapy comparator. There's not enough BCG to compare to. We might do investigator's choice. If you look at SunRISe-5 and the J&J SunRISe programs for BCG experienced patients anyways, they're allowing investigator's choice of gem or mito. There is precedent for that being at least a reasonable comparator. The big question for us is LGIR. That's a big addressable market. It is competitive. Are we differentiated enough? Is our profile, safety, tolerability, ease of administration, is that an option for us? We will take a look at both of those sort of in that order in 2025. Of course, there's the systemic piece, which we're the only investigational agent out there in the NMIBC setting that can be administered systemically.
What we want to do is push the envelope on the maintenance side and say, once radical cystectomy as a major unmet need is diminished because of all of these cool, innovative products in the NMIBC setting, where is your residual unmet need? It is the administration of transurethral drugs. Imagine a world where instead of two years of transurethral maintenance of whatever product, you could do a sub-Q dose of 002 and not ever have to invade the bladder. That is a world that we want to increasingly explore in 2025 as well.
OK, very provocative. OK.
That was it.
That is it? OK.
Thank you.
All right, of course, we have a lot of other pipeline agents that we didn't get to cover, but looking forward to the progress that you all are kind of.