Okay. Good afternoon. Thanks so much for joining our 6th Annual Oncology Innovation Summit. I'm Stacy Ku, Senior Analyst on the biotech team, with my colleague Vishwa Shah. We'd like to welcome Jackie Zummo to our discussion. She's the Co-founder and Chief Scientific Officer at Protara Therapeutics. Jackie, thank you so much for joining. Thanks for the rest of the Protara team, Jesse, Patrick, and Justine. There's a lot of investor interest in NMIBC, and we're very excited to discuss TARA-002's recent and upcoming updates. Just real brief, Jackie, for a quick introduction, can you provide some background on the lead program 002? What makes it similar to BCG, and in what ways is it different in terms of MOA and administration?
Yeah, sure. Thanks for having us, Stacy. 002, it's an investigational genetically distinct strain of Streptococcus pyogenes. It's inactivated through a proprietary manufacturing process that allows for it to retain its immune-stimulating properties. You know, we've been manufacturing 002 for several years now. What we do is we originally took the master cell bank of OK-432, and that's the originator that's approved in LMs and a number of other oncology indications in Japan. We developed 002 from that same master cell bank. We've got worldwide rights, excluding Japan and Taiwan, for 002. As far as sort of how it is mechanistically the same and different from BCG, I'll start with its similarities. Both are bacterial immune potentiators. They both drive a Th1 pro-inflammatory response.
They both have preference for M1 polarization, which is known to be critical for anti-tumor immunity in bladder as well as other cancers. Where they differ is that 002 is a NOD2/TLR2 agonist. BCG is a TLR4 agonist. We've done our own work to compare 002 directly to BCG. We've done this in vitro. What we've found is that 002 results in a significantly stronger tumor cell killing compared to BCG. It also results in significantly higher upregulation of key pro-inflammatory cytokines and chemokines, including TNF alpha and interferon gamma. Another important distinction is the downregulation of IL-8 that 002 elicits. We know from the literature that IL-8 is associated with bladder cancer recurrence. We see BCG having to be known to be an upregulator of IL-8.
When we've done nonclinical experiments in animals, we've sort of seen all of that kind of in vitro work sort of play out. What we, in addition, see is durable responses that are around 70% of mice being still sort of cancer-free at the 60-day mark. We sort of relate that to 002's broad anti-tumor immunologic profile and its potential to result in durable responses, which are clinically meaningful. We've now also, with our clinical data, started to see that in the clinical trial setting as well.
Yep. Of course, still early days, but still does suggest that it is somewhat differentiated to BCG, especially in the first-line setting. Definitely, in our view and based on KWOL feedback, kind of in a BCG-unresponsive patient population. Of course, we've gotten some early data so far. As we approach the key readout in BCG-unresponsive NMIBC patients by year-end, maybe talk about your own efficacy expectations in the context of the data that you've already shown at 6 and 12 months. What kind of CRR would you expect is competitive?
Yeah. We expect to share data on 25 BCG-unresponsive 6-month evaluable patients towards the end of this year. Some of these patients are going to be evaluable at the 12 and 18-month time point as well. We will be able to see continued durability readouts in those patients. I think based on the MOA of 002 and what we have seen in the initial data set, there is a really good potential for 002 to continue to have durable responses as the sort of total population exposed increases. As far as efficacy benchmarks, I think there is sort of a cadence of what is considered competitive. This is a pretty dynamic landscape. It is changing on a regular basis with multiple investigational drugs and even new market entrants.
What we see is that at about the 12-month point, you need to be about a 30% CR to really be in the game. I think that gets you sort of used third or fourth line. What we see so far, 40% is pretty competitive. If you're at 50% at 12 months, I mean, you're best in class. No one's there. I mean, Credo and the Pretzel are around a little under 50%, around 46% each. That, to us, is sort of what we're aiming for. I think with this specific mechanism of action, we're hoping to be somewhere between the 40%-50% like what you see with the other immune potentiating drugs and even with TAR-200 as a cytotoxic.
Okay. Understood, understood. That makes a lot of sense, especially as you point out that it's a dynamic market that's kind of changing in real time. Maybe also talk about the reinduction and the findings you've seen so far. Other companies have talked about the importance, especially to get a durable response. Maybe talk about the results you've seen so far. Do you believe they're differentiated to other agents?
I think that all immune potentiating drugs have the ability to allow for reinduction. I mean, we see it with BCG. We see it with Credo Stamagine. We see it with all of them. Engine is now starting to sort of ensure reinduction across their patient populations. I think that what the most important thing is to focus on when it comes to reinduction is that this is an endpoint of complete response. We do not have recess criteria. That is complete removal of any disease, disease-free. There are patients who are going to have persistent CIS 12 weeks later. In the real world, physicians do not change that treatment just because there is some residual CIS. They challenge again. I mean, that is what BCG and that is what the AUA guidelines tell physicians to do in that case. Not every patient is going to require that.
What we see in our data set is that there are some patients that have residual CIS or persistent CIS that do require another induction course or reinduction course. There are patients that do not, and they are a complete responder at three months. They have the ability to go on to maintenance treatment. I think that what is nice about these immune potentiating drugs that allow for reinduction is that you have the opportunity to really be able to make a determination whether or not a patient needs to be changed off of a medication at the 6-month point. I do think that what we are seeing is that for those patients that require reinduction, it is meaningful because they are able to convert to a complete response at 6 months. That, I think, is true of all of the immune potentiating drugs.
It's true of BCG as well.
Okay, okay. Understood. Again, laser focus, I know from your team and investors as well on how we're approaching kind of that readout. Maybe talk about how enrollment is going, provide any updates on progress. Of course, as we add it to the mix, maybe discuss expectations for enrollment split in the CIS versus concomitant cyst papillary patients, especially in that BCG-unresponsive cohort.
Sure. I think for us, what I'd like to focus on first and foremost is that enrollment is going very well. We sort of took a step back and looked at our geographic mix, our site mix in the U.S. early in 2024, and put together a strategy that addressed sort of the shortcomings that you have in the U.S. sites where you've got really long IRB timelines in the academic centers. Those are sort of the places where these patients are being treated. Just what can you do from an international perspective to be able to get through regulatory timelines that are reasonable XUS so that you could get sites open and active and be able to start contributing in a meaningful way? We started that in early 2024.
Now we're really starting to see all of that kind of come to fruition. We're excited about what we're seeing. We continue to expand geographically. We're 30 sites in the U.S. right now, a mix of community and academic approvals in Japan, IND accepted in China, South America countries opening. We're really pushing for our ability to have this study fully enrolled by the spring of 2026. From where we are right now, that looks like that's a very, very tangible goal to have.
Okay. Spring 2026 it is. Okay. Wonderful. Maybe that split on CIS and concomitant CIS papillary patients, especially as you're trying to be really selective for your patients, obviously keeping in mind all the baseline characteristics, including kind of whether or not they're CIS pure versus concomitant disease.
Yeah. I think all of these studies you see because everybody looks at this, the baseline sort of diagnosis at baseline. The majority of these studies have a heavy slant towards the CIS-only population. I think that our study will be consistent with every other study that's been conducted in this patient population. I think that when you look at the way that these studies are designed and the inclusion exclusion criteria, you're pretty consistent. You've got the FDA guidance to industry that tells you what the definition of BCG-unresponsive is. Then you've got the AUA guidelines to sort of guide you to help to ensure that you're really putting the right patients into a trial. What I mean by that is a patient who may have the opportunity to actually benefit from an investigational drug. That's how we approach this.
I think we will probably see a very, very similar split CIS, CIS plus concomitant papillary disease to what everyone else is seeing. I think that's not because of management of the patients coming in. It's really about the patients that are right to come into a trial.
Okay, okay. Understood. So it's a bit of is it fair to say sweet spot is maybe around 75% cyst, 25% concomitant?
Yeah. I think that's probably where we'll be. I think pretty much everyone is around that spot. I think some are higher. Some of the approved products have been a little bit higher on the concomitant papillary. Yeah, I think that's a reasonable assumption. I think that's probably where we'll end up.
Okay. Understood. Maybe talk briefly on the nuance of the patients that you've enrolled so far, especially as we think kind of move to the bigger picture question on opportunity and the types of patients that might elect for third or fourth line types of treatment. Really, these patients have prior chemotherapy use. How many lines of treatment do they usually try before they kind of move to a cystectomy?
Irrespective of whether you look at a claims database or you have a conversation with the urologists that are treating these patients or you have a conversation with Beacon, the number one thing that every patient is trying to avoid is cystectomy. I think that you will see a patient want to try as many lines of therapy as they possibly can to avoid that surgery. It's really up to the provider to make a decision as to at what point does it become more of a risk and less of a benefit for them to try investigational drugs or to try approved products. Johnson & Johnson says that this is an addressable market of around $5 billion. They've got a lot of smart people over there. I think that they're probably correlate to the number of patients that are potentially able to be treated in the space.
I think there is clearly enough of a variety of modalities and mechanisms in this space that are all being developed that gives the opportunity for multiple lines of therapy in these patients who are trying to really avoid this morbid surgery. I think that physicians will start to think about and you will start to see that the conversation drives towards how do you sequence these drugs. Do you go from an immune potentiator to a cytotoxic back to an immune potentiator? Do you combine an immune potentiator with a cytotoxic? That, I think, is going to be the way that the conversation goes over the next couple, I'd say, months and years when we start to get more approved products and the real-world treatment of these patients come into play.
Okay. Remind us, for the patients that you've enrolled so far of which efficacy you've disclosed, how many lines of treatment are they typically cycling through before they come to a study like yours?
Yeah. So we've got two cohorts. The BCG-naive, I mean, they're BCG-naive, but they're not completely naive to treatment. I want to say about 40% of our population is completely naive to treatment. That means that they would have received chemotherapy, maybe pembrolizumab, or BCG, but not for the last two years. In the unresponsive arm or cohort of our study, it's similar. Obviously, they've all had BCG, and they've all had adequate BCG, or they would not be able to come into the trial. We do see that we have patients that have been treated with multiple lines of therapy, including some of the newer approved products. None of these drugs are a cure. You're going to have more patients that are going to have failed therapies that are coming into these clinical trials.
The question becomes, what is your drug able to do? Because we all know that as a patient is treated more frequently and then does not necessarily have a response to treatment, they become harder to treat. What we are seeing is that those harder to treat patients, when they get 002, they are actually responding and doing really, really well. That, for us, is really encouraging.
Okay. Awesome. Again, obviously, as we go big picture and talk about the avoidance of cystectomy, maybe talk about the opportunity for TARA-002 as we look at the nuance between maybe those prevalent patients of those that are cycling through drug versus maybe a more traditional way that we try to model out a market, which is the more narrow incidence kind of number of patients for NMIBC. In your view, what are the number of patients in that prevalent population that might be a target for TARA-002 in the BCG-unresponsive population?
I think the numbers, depending upon who you talk to or whose slide deck you're looking at, kind of bounce all over the place. I'll give you my perspective as it relates to just recurrence rates and sort of what we see. If at best, you've got 50% of patients that are disease-free at 12 months, then 50% of those other patients, the other half, are going to be able to be in a pool of patients that could potentially be treated. I think that that number is going to potentially stay pretty consistent because we haven't seen any, we haven't really seen any treatment option that's been better at 12 months than 50%. Bring them into the fold right around the time that you would expect a patient to be recurring. That's when sort of you'd have the ability to switch off.
I think that that's where the cycling conversation or the sequencing conversation sort of starts to come into play. It's what do you then give that patient? I think there's about 65,000 high-risk, high-grade patients in the, I think that's one of the numbers that have been thrown out there. How many of them are CIS? How many of them are CIS plus concomitant papillary that fit into the narrow definition that the FDA sort of defines? I think that this is all to say that there is a large number of patients out there. Who's got it right? I think it depends on the database that you look at. I also think that it's going to be about, from a future perspective, just how well these drugs perform at 12 months, 24 months, 36 months.
I think that just based on what has been said to this point about the patient population, it's large. They want to avoid a radical, morbid procedure. I think that the population probably stays the same, grows a little maybe because we'll be avoiding cystectomies with some of these newer drugs.
Okay, okay. Understood. Maybe let's talk about the competitive landscape. We kind of discussed it really briefly, but where do you think TARA-002 could slot in? And again, what sort of advantages do you have for TARA-002 in terms of administration, especially as we think about the urologist that's caring for these patients a little bit different than maybe a typical medical oncologist?
Yeah, absolutely. I think a couple of things about 002. Efficacy has to be there. No physician is going to use a less than effective drug if they have other effective options that are sort of tolerable and can address a need. 002, I expect to have similar, if not better, efficacy than what we're seeing either investigational or approved today. I think durability will be in line with the other immune potentiating drugs. I think that one of the things that is going to be key here from a patient preference perspective is going to be the tolerability profile. We already know from our PIs that this is a drug that is very tolerable and that they do not think twice about giving to their more frail, older population that they're treating.
Take safety and efficacy out of the frame because it's sort of table stakes and a given that you need to have those. Ease of administration is definitely going to play a role. Anything that doesn't disrupt the practice, anything that allows for a treatment option to sort of slot in without having to cause disruption, new training, special handling, new rooms, all of that is, I think, going to be a benefit for 002. I think that these are primarily patients that are treated in the community setting. The community setting does not necessarily have the ability to sort of make all of these changes or sort of address changes that need to be made to bring a treatment in. It's just not really worth it for them.
I think 002's advantages from ease of use perspective will definitely play a key role in rapid adoption from the provider perspective, but I think also rapid sort of patient preference just based on the tolerability profile.
Okay, okay. Understood. Obviously, a lot of focus from all of us on BCG-unresponsive patients. Can you talk about longer-term developmental plans, maybe for first-line positioning of TARA-002 versus BCG? Maybe talk about when we get an update and what might be underappreciated for the efficacy we've seen so far.
So far, in the BCG-naive setting, our six-month CR rate's 63%, 12 months is 43%, and our CR at any time is 76%. That is with 50% of patients being concomitant papillary patients. We are very encouraged by those data, especially in a front-line setting. Looks a lot like what BCG is. I think that is really encouraging to have as a potential alternative to BCG. I do not think that any current investigational or approved product replaces BCG. It has been the standard of care for a really long time. There are a lot of patients that do not have access to adequate BCG therapy. They cannot tolerate it just for reasons related to their own situations. I do think that alternative treatment options in the BCG-naive setting are necessary.
I think that if you look at the Beacon think tanks and where the FDA has engaged around discussions in the BCG-naive setting, they're also looking to and acknowledge that alternatives are required. For us, our next step, now that we do have proof of concept data, is to engage the agency and have a conversation with them around what does a registrational study look like. We know from the update to the FDA guidance to industry in August of 2024 that a randomized controlled trial is required. The question is whether or not they are past the point of needing to have a non-inferiority study to a drug that's in shortage, that isn't available to everyone, can't be accessed, can't be tolerated, all these things, to accept that there are other standard of care options.
I call them standard of care options because we just undertook a pretty large real-world database analysis with one of the three largest payers in the country. What I can tell you is that almost just as many patients with a CIS diagnosis get BCG as get some form of a chemotherapeutic product. It could be mitomycin. It could be gemcitabine. It could be gemdosi. The point that I'm trying to make is that the standard of care of BCG, as long as you can tolerate and you can access and you can have adequate, it's an amazing drug. It does amazing things for patients in terms of efficacy and safety. There is a good percentage of patients that do not have that opportunity. We would like to be able to be an alternative. We're going to engage the agency Q3 of this year.
Hopefully, we'll get feedback that aligns with what our expectations are, and we'll be able to roll that out. I mean, our proof of concept data is very encouraging.
Okay. Is it fair to assume that when you're engaging with the FDA, you're hoping to maybe use the comparator arm of chemotherapy?
Yeah, I'd like to be able—I mean, yes, I'd like to be able to propose to them that based on the real world and what's really being done to treat these patients, that despite it being BCG being the standard of care, there are other alternative options that are being used out there as standard of care that actually might be an acceptable comparator. Look, they may say, "We agree with you, but we still think that you need to have some exposure to patients that are BCG that could potentially get BCG." That becomes a statistical argument and whether or not we'd be able to power that study appropriately.
Okay, okay. Understood. In the last few moments, maybe just a reminder, and you all have three programs in total. So just a reminder of upcoming catalysts and when we'll get next updates for everything.
Sure, sure. I think we're most excited about the end of the year, the 25 patients in the BCG-unresponsive setting that'll be six months available. As it relates to choline, we're in rapid startup for our registrational 2B3 study. We expect to have some data towards the end of this year on that first dose confirmation cohort. We're excited about that. LMs, look, our wait lists are full. We're actively dosing. Our expansion cohorts are enrolling. We're seeing really positive, encouraging data coming out of that study. I think towards the end of the year, we'll be happy to update everyone on that as well.
Okay. Wonderful. With that, we're going to conclude our discussion here at Protara Therapeutics. Thanks so much for joining us today, Jackie, and thanks to all the investors, Jennie Ann.
Thanks, Casey.