Hey everyone, welcome to our next session with Protara Therapeutics. My name is Lee Walthek, a biotech analyst here at Kenter, and it's my great pleasure to have Jesse here with us today to talk about the story. I think Protara has a really interesting, you know, sort of setup. You guys have sort of two franchises, one in oncology, particularly bladder cancer. You also have a vertical in rare diseases. We're going to talk, you know, both of them today. Before that, I want to maybe hand it over to you to give us a quick overview.
Sure. Thank you, Lee, for having us, and thanks to the Kenter team. Protara Therapeutics is a development stage company focused, as you said, on oncology and rare disease. I think sort of our special sauce is our approach to how we've built the portfolio and how we prosecute the portfolio in the clinic. That is, we try to reimagine known mechanisms of action under the umbrella of evolving science, evolving regulatory pathways, evolving manufacturing, any sort of location in the drug development and even potentially marketing continuum that could be applied to an asset that already has sort of established biology, established mechanism, that allows us, in theory, to drive an accelerated development and commercialization pathway. To us, our North Star is Revlimid, right?
Started out as thalidomide, and then was shelved for years, a lot of documentaries about it, and then suddenly it becomes a $6 billion a year hematological cancer product when it was reimagined. That sort of informs the way we have built the portfolio. As you said, we are in registrational studies for our TARA-002 program, which is a genetically distinct strain of Streptococcus pyogenes that we inactivate and therefore can administer intravesically in the case of NMIBC, systemically. This is a therapeutic whose predecessor, OK-432 in Japan, has been utilized in tens of thousands of oncology patients. Obviously, we know that it's oncolytic. The reimagining there is the massive amount of information that we've learned about immune oncology in the last two decades. There we're sort of applying those standards.
In the rare disease portfolio, we have IV choline chloride, which is a phospholipid substrate replacement therapy for patients who are on parenteral support. That is also in a registrational study. Finally, TARA-002, different formulation, different dosage, different administration, for patients with lymphatic malformations that are specifically macrocystic or macrocystic dominant. There's a lot going on across that, but when you look at the Protara management team, which has expanded this year, everyone on the team, myself included, comes from or are pedigreed by previous roles in companies that had multiple shots on goal. For me, when I left investment banking and moved into the biotech world, my first job was at Vertex, right? Over here we were developing and marketing INCIVEK, the first direct-acting antiviral for HCV, but over here we were working on cystic fibrosis, right?
That sort of the breadth, if you will, of the portfolio is not new or novel to myself or the management team. We feel pretty equipped to prosecute all of them. So, mm-hmm.
Yeah, that's great. Maybe starting with NMIBC, obviously a ton of investor focus here, and you guys showed some really great data earlier this year, in April. Maybe just walk us through what you showed so far. I understand there's a pretty big data update coming up as well. It would be great if you can set early expectations for us.
Yeah. In April, we showed what I would call sort of a continuation of our sort of first real data release, which was in December of the previous year. Notably, in April, the data we put out covered both BCG-unresponsive carcinoma in situ, plus or minus papillary. Anyone in the space knows this, like, yeah, a scripture. We also were the first sponsor to put out a data set in BCG-naive patients. Just to sort of long story short, the BCG-unresponsive cohort was a small n, but we demonstrated essentially a 100% complete response rate at any time, about 80% complete response at the six-month time point, and 60%+ CR at 12 months, which to date, as all of these investigational programs go further and further out with their data sets, the bar tends to want to move along with the longest term data.
What you can expect six months later from April is that this next data release will include 18 months data in the BCG-unresponsive as well as in the BCG-naive arm. Just a quick word on the naive setting. That was a larger N, and in it, we were able to demonstrate the differential responses that we had always anticipated between CIS only and CIS plus papillary. There was a more representative sample in the naive cohort. That gives you, if you will, a breadcrumb trail in terms of if the difference in the naive, more interpretable cohort between CIS and plus papillary is replicable in the BCG-unresponsive setting, where at that point we had only shown data on CIS. We're not going to stay at 100%.
Inclusion of CIS plus papillary, which I can tell you we have enrolled many, many more CIS plus papillary patients than we had shown before in the unresponsive arm, gives you a sense of what that differential is in response rate, and it can kind of guide you to where you think the final response rates at six and 12 months, which are our regulatory endpoints, might land. If that differential holds true over in the unresponsives, then we would remain, I think, at a very competitive response rate.
Okay. What does competitive response rate look like?
Yeah. Let's pretend that this is not an indolent chronic disease setting and that product profile is ultimately kind of what's going to drive adoption. I've always thought about it, and I'm happy to be disabused of this view. I've always thought about it as there are sort of three thresholds of relevance. The first threshold of relevance is, will you be in the conversation, right? After you've tried a bunch of things, you can try those. What is really competitive and then what's best in class. To me, again, six and 12 at a six-month landmark, I think you've got to be in the fifties to be a part of the discussion in terms of 50% complete response at six months. I think sixties, low seventies is you are right there with every other competitive product.
Anything above kind of 75% in something with an eight in front of it is a category killer at the six-month time point. As I said, the relevant time point for evaluation has moved out, and I think 12 matters. For us, 12-month response rates, again, in that framework of part of the discussion, right there, competitive to everybody else, and then best in class. To me, that's sort of 35% mid-forties, and then anything 55% or better is tangibly different than what's out there from a competitive perspective.
The next big update is obviously in the BCG-unresponsive patients, so 25 patients. In Q2, I believe you pushed out the timeline a little bit to Q1 next year with end of this year before. Maybe give us some context in terms of the timeline shift.
Sure. It's more about the audience than the data set itself, if you will. If you looked in April, we effectively had 17 patients enrolled in total in the unresponsive arm, right? Go out six months, those patients again are going to be at least six-month evaluable. A lot of them are reaching their six-month evaluation time point in the month of December after the SUO conference. Our objective is wherever possible to give our investigators the opportunity to present our data at the podium and to do it under the context of a medical conference. I think that obviously, there's a lot of benefits to it I don't need to go through, right? You would rather be a part of the discussion in the framework of a medical conference.
For us, the most proximal medical conference to SUO is GU ASCO in the middle of February, and you probably should expect to see something at that conference.
Okay.
One other thing I'd like to say.
Yeah.
We will, at SUO, publish data on the ongoing 31 patients in the naive cohort of cohort A of advanced two, right? Those are patients, A, remember I already said that that was a larger, more interpretable data set as of April. We are going to get longer term data in those naive patients. I think the naive opportunity remains a pretty big discussion around 002 and its ability to sort of, or our ability to prosecute a, you know, piece of the NMIBC puzzle that not everybody is looking at at the moment.
Okay. Now, in terms of, you know, this is only patients in this 25, BCG-unresponsive patients, do we have a sense of percentage? Is 80%, 70%?
We're not disclosing anything.
You're not disclosing.
No, but I can tell you that it's not going to be CIS only.
Okay, because I was just going to work out the math for a response rate right here.
How about this, Lee? This is literally the way I'm looking at my amazing CFO right now, Pat Fabbio. When Pat and I nerd out on this, and you know, with Excel, I'm sure that the world has moved beyond Excel. I'm a dinosaur in that regard. Here's how we think about it. If you look at the percentage of CIS patients enrolled by our competitors in both approved products and their registrational data set, as well as the intentional registrational data set of two of our competitors that are kind of in front of FDA or about to be in front of FDA, take a look at the percentage of CIS only enrolled in those data sets and really pay attention to the competitors out there that are addressing NMIBC via an immune-mediated treatment paradigm, right? 70% - 75%.
As high as 82% and sort of the lowest, I think, is Keytruda's approval where they were at 68% CIS only. Let's say that we set that as a goal for enrollment. You would do 0.7 times whatever the CIS response rate is and 0.3 times whatever you think the transferable response rate is in concomitant papillary, and that should give you your response rate, start with a seven.
Okay. We generally use ChatGPT for the math.
Still learning. Still learning.
In terms of competition, obviously CG and G&G are ahead of you, and I think many investors just look to them as sort of the benchmark. I believe 002 has other differentiating factors. Maybe you can walk us through that.
Yeah. At the end of the day, let's talk about where the average NMIBC patient is treated. We have over the years made great utilization of claims, right? Let's actually look at data that FDA agrees with. You're talking about Optum. FDA accepts Optum data as sort of representative of real-world statistics. 80% of all intravesical medicines historically are administered in a community practice. Therefore, the objective of a community practice is an individual that's hung a shingle, for a surgeon that's hung a shingle, and that's how they make money. Further, 20%, this number might, 20% of all large urology group practices at this point have been rolled up by private equity, right? Let's just say as an assumption, let's agree that those urology group practices are focused on economics, perhaps maybe more than academic centers, which the numbers suggest are about 20%.
We, as a rule at Protara , when we think about a program, we actually start with, can we make it, right? A thousand ships have crashed on the shoals of manufacturing CRLs. On top of that, is this an actual product? That has always informed, and it's equally important to us as is the design. Obviously, you want to design a study that wins. From our perspective, 002 is a great product for these practices. What does that mean? Number one, it is administered exactly the same way as BCG. You do not have to retrain your nurse. You don't have to retrain the nursing staff or the pharmacist. It handles and is administered exactly like BCG. On top of that, the time to administer via catheter is 15 minutes, right?
When you're thinking about a procedural-based practice, the number of procedures drives those economics that are increasingly important in that setting. There's that. On top of that, we know that effectively, a number of cystectomies are going to go down because there are all these novel therapeutics that are coming into the market and a lot of different choices for physicians. Those patients are going to be living with this highly recurrent indolent chronic oncology, you know, kind of diagnosis well into their eighties as a result of, you know, these drugs having better response rates once patients are refractory to BCG or even when they want an alternative to BCG. There, the safety and tolerability profile of TARA-002 comes into play again. Very well tolerated, very easy on the patient. There are no post-administration requirements.
Many of our competitors have, you know, the requirement of urine bleaching for 24 hours. When you have an 84-year-old patient, you're now talking about not just that patient, but the adult children of that patient or a caregiver that have to sort of drive adherence to the protocol of a live oncolytic virus or BCG or what have you. It's just a lot easier across the spectrum of practice and patient. The other piece that I would say is we have extraordinarily low cost of goods sold, which gives us a lot of degrees of freedom to drive home the advantage of 002 from a trade and distribution perspective, right? We won't ask physicians to pay us first before they get reimbursed. That's the kind of thing that will change a lot of behaviors of physicians.
What about enrollment? I mean, you've had challenges in the past, but what are you seeing in terms of the patient enrollment pace?
You have to think about enrollment in the context of the right patients coming into your study. Are these patients going to benefit from this drug, right? Sometimes you have to make tough decisions on that front. Let me answer your question directly. We are enrolling as we have expected, and what we're seeing is it's still very competitive for the BCG-unresponsive CIS, or just the epi works against you. In the U.S., remember that in BCG-unresponsive, BCG shortage makes it harder. If you look at some of our competitors, their sites are 25% U.S., 75% international. We have been adding international sites like crazy, and our enrollment is in line with our expectations.
Okay.
As we continue and think about the sort of naive setting, the BCG kind of alternative approach that we want to take, if you look at our enrollment of that exact patient type in cohort A, our 30, you know, we were originally going to enroll, I think, 25 naive patients, but there was so much demand, we over-enrolled up to 31. If, you know, once we're able to sort of talk publicly about where we are on that BCG alternative pathway, the eventual study that we may or may not do there would have a very different enrollment profile.
Okay. I think there is another sort of question on the regulatory pathway. If the accelerated approval path will still be open by the time you guys generate data, just given there are some interesting changes at CBER right now. There is more focus on single-arm study to support accelerated approval. On the other hand, maybe there are more therapies going to be approved in this setting. What is your take on that?
Yeah. Look, I think anybody that brushes off that question is being irresponsible, right? This FDA has demonstrated that they can throw you a curveball, right? There have been some recent CRLs given to trials that were run exactly the way FDA outlined it. A couple of things that I would say I would point to that give us comfort. One is factual, and one is you got to sort of believe alongside me with that. The first is, if you looked at UroGen's more recent ODAC, one of the participants at the ODAC sort of raised, should we be doing RCTs for everything? Another one of the participants said, oh no, no, no, no, no, but not in high risk, high grade BCG-unresponsive. The BCG-unresponsive is still single-arm open label, right?
I believe that was in either April or May, or I'm sorry, that was even more recent than that. There was a lot of agreement on the line during that ODAC for the appropriateness of a single-arm open label study in the BCG-unresponsive setting. The second is just if you look at oncology settings in general, a standard of care has to kind of be established before FDA will say, okay, you got to compare to this because it's been a while now, and this is the standard of care. We've had three approved products in the BCG-unresponsive setting for a while now, and none of those have been required to be comparators in any of the studies that are underway now, whether it's J&J, us, CG, NG, you name it. That has been FDA's behavior so far.
They believe, and I think we can all agree, that no standard of care has been established. In general, if you look again at other oncology settings, it takes about 2 years-3 years of one or more competitors duking it out before FDA starts to say, okay, that is the standard of care.
Yeah.
Here's the thing. I think we're, yeah, look, our expectation is that we will be long fully enrolled before one of these novel therapeutics that are intended to come to the market may or may not become standard of care.
Yeah. I think if you look at the recent example of Precision approval, I think, you know, Prasad has said, you know, there is certainly some flexibility there
Yeah.
That's the new Prasad we like to see. In terms of, you know, BCG-naive registrational trial design, I know you guys are going to have some news for us maybe by the end of the year in terms of where you are with the FDA. What are the parameters that you're still trying to align with the agency here?
The answer really lies with what did we go to FDA with as our target patient population in the naive setting. I think, just taking a step back, the utilization of BCG and its sort of role as standard of care in this setting is fantastic, right? That is a drug that works. It's got a lot of drawbacks. Physicians always are looking for something new, but in general, it's cheap and it's effective. Merck may or may not live up to its claims that it's going to increase capacity. What we know is that even when there were two suppliers of BCG in the market as recently as 2017, even then BCG was in shortage. There will always be, I think, sort of a varying supply of BCG. We didn't go to the agency and say, I want to replace BCG.
What I want to be, and this is based again on claims data that we took a look at, cut through the data, seven years' worth of claims. What we observed is approximately 35% of patients who would otherwise be BCG eligible get something different. That something different is usually chemotherapy, almost exclusively. If we want to slot in a, listen, if for whatever reason a patient doesn't tolerate, refuses, or can't get BCG or is contraindicated for BCG, those sort of four buckets, we represent a pretty great alternative. That's what we went to the agency in terms of this is who we want to look at. Therefore, if those patients would otherwise get a chemotherapeutic, our argument is that in an RCT to demonstrate efficacy in this BCG alternative patient population, then the comparator should include minimal, if any, BCG.
It's the comparator that we are still kind of engaged with FDA on and should have an update on that definitely before the end of the year.
What proportion of the patients will fall into these sort of four buckets?
Yeah, we don't break it out, but, you know, look, can't get BCG is probably 50% and 50% is refuses, doesn't tolerate. If you go to the BCAN website, BCAN being the Bladder Cancer Advocacy Network, that's where you're seeing a lot of patients express sort of their sentiment about what treatments they are willing to accept and not. There's a lot of patients out there that if given the alternative, they would not elect to undergo BCG treatment again. Think about that. That's a patient that was given BCG, it worked, greater than two years later, they recurred, and they're still BCG eligible. If you present those patients with an opportunity for something different, a lot of them are going to raise their hand.
Maybe switch to IV choline program. Where are you in terms of the THRIVE-3 trial?
Yeah, we are frustrated with the enrollment in THRIVE-3 . I want to kind of break down what that relates to. THRIVE-3 starts, it's a phase II- B3 seamless design. I'm going to try and go through this quickly. The first arm is sort of a dose confirmation arm, testing three different doses in 24 patients total. We'll be looking again at that sort of PK-based primary endpoint. We'll follow those patients through to the secondary endpoints at 24 weeks, and then even further in an open label extension, which would eventually, I think, probably morph into sort of a patient registry or something similar to that. The PK-based endpoint, right, without even a numerical threshold to achieve, is obviously a pretty big win when you're talking about a registrational study as primary endpoint.
That requires an overnight stay at a facility for rich PK sampling through the course of the evening as those patients are being infused with their parenteral nutrition and IV choline. In the U.S., that's been tough. We've got sites that are available and ready to kind of get through IRB and all that sort of stuff, which in its own right is frustrating. Now you're competing for beds in the U.S. That's frustrating. Let me sort of talk about the bright side. We have always known that this is a study that is going to enroll significantly more patients in Europe. Why? Because parenteral support patients in Europe are treated at catchment centers that are devoted specifically to managing patients on parenteral support. In Denmark, there is one hospital, and that's actually one of our highest enrolling sites for THRIVE-1 . It's Palle Jepsen.
He's been in the short bowel syndrome space for a long time. The reason is he's got 300 + patients on parenteral support. Those patients, if they come into that site, don't have to sort of negotiate for a bed because there are only beds for parenteral support patients in these European catchment centers. The silver lining here is we got approval to enter every EU country and do so, you know, kind of enroll as quickly as you can, or as, you know, there's no sort of, but, and like Europe is wide open to us, and that came three months earlier than expected. We're starting to see some of those European sites come online, and when they do come online, they don't talk about, yeah, I've got four patients I can contribute.
There's a site in France that has 500 patients on service, and that investigator was like, I could just enroll your whole study, right? Europe is the silver lining for us in what has been frustrating. This is the first parenteral support kind of study that's been done in the United States. Since maybe the parenteral support components themselves are trace elements, it's been a long time since a new agent has been introduced into this setting. We're learning as we go from the U.S. Luckily, there's a lot to lean on from the European perspective.
Okay. It's great to hear that you guys seem to have very great, you know, momentum in Europe. Any sense on when you might be able to enroll that 24 patients and we might see the initial data?
I think that a good frame of reference for enrollment of the 24 patients is probably by kind of middle of the second quarter of 2026. It could go a lot faster. Again, once one of these centers opens, you don't know if you're going to get 15 patients, and then you have to say, okay, I need a little bit of diversity. I think right now, in terms of getting a good read on the primary endpoint, you should be thinking about, from those 24 patients, you should be thinking sort of the summer of 2026.
Okay. We don't have a lot of time. Maybe, Jesse, the top two or three priorities for you guys over the next year.
Top two or three?
Yeah, I know you're thinking.
Enroll, enroll, enroll.
Okay, we got the message.
Thank you so much.
Thank you.
Thanks, Lee.