Great. I'd like to welcome back everybody to HC Wainwright's BioConnect Conference at NASDAQ. My name is Andres Maldonado. I'm a biotech analyst here at the firm, and it's my pleasure to welcome Protara Therapeutics next. From the company, we have CEO Jesse Shefferman. Welcome, Jesse.
Thanks, Andres.
Yeah, really a pleasure to have you here, and I always enjoy speaking with you about the landscape. Let's start from the top. For those less familiar with the story, can you walk us through the company's focus areas and how the lead asset, TARA-002, fits into the broader vision across oncology and rare disease?
Sure. So, you know, as a general overlay, Protara was founded in 2017 by myself and my co-founder who just walked in with the idea of trying to find the next Revlimid. Are there known mechanisms? Are there interesting molecules out there that apparently had, you know, sort of extinguished their useful life, but could you re-envision them in a different lens? And that could be, has the biology changed? Have the assays changed? Has the regulatory pathway changed? Has manufacturing changed? There are so many ways that this industry is constantly evolving that creates opportunity to sort of rethink sort of what has been dogma. And so when we licensed in 002 from Japan, 002 originally was approved in Japan in the 1970s under the name of OK-432.
It is a bacterial immunopotentiator from the Streptococcus pyogenes family that is rendered completely inactive, so not attenuated, which we all know a great comparator is BCG. We felt that the field of immune oncology had moved so much, and we had learned so much across the board in that setting that pretty much everything we knew about OK-432 was up for debate. We systematically, once we got the rights to OK-432, we have to call it 002 in the States because in Japan it's approved, here it's not, but it is exactly the same drug as OK-432. You asked, where does that fit across the portfolio? Thematically, I want to go back to this idea that every component of our portfolio benefits from some level of risk containment. You can never eliminate risk, but you can sort of better qualify or understand it.
In the case of 002, this bacterial immunopotentiator that drives a massive immune response, not dissimilarly to BCG, in the NMIBC setting, right, this is a drug that has a 65,000 patient safety database. We know that it's active against solid tumors. We know that it's immunoactive. Where is there opportunity? NMIBC. Standard of Care is also a bacterial immunopotentiator. You don't have the adoption of 002 in that setting is not necessarily a heavy lift. Across the portfolio, that's the de-risk piece there. It works in cancer. We know it's safe, and we know it's immunoactive. Now that we have gotten to the point where we're looking at, you know, longer-term durability in our NMIBC program, some of the theories that we had about its utility in NMIBC are bearing out.
In the case of our other program, IV choline chloride, phospholipid substrate replacement therapy, that came to us from an inventor-founder who had run a fairly well-constructed phase two study where he was able to demonstrate significant increase in serum choline concentrations for patients on parenteral support. You know, the sort of the guidelines for parenteral support, both in the U.S. and in , call for a product to restore choline levels in these patients, and we can get into some of the, you know, the biology there. There's that piece of de-risk. The final one, 002, again, at a different dose, different administration in a rare pediatric non-malignant disease, lymphatic malformations, it is the standard of care in Japan with a huge experience in multiple investigator-led studies around the world. We're conducting a single-arm open-label study across a number of different age categories.
There's an interesting rare disease opportunity with a PRV assigned to it. All of that is to sort of illustrate as you look across the portfolio, we believe that we can define the risks associated with each of these and contain those risks as we get through development. At this point, we're in late-stage development across all three.
Great. Very helpful. Thank you for that overview. My next question, I'm really excited to get your take on it. Muscle-invasive bladder cancer, you know, has become a hotbed of innovation in recent years with multiple new entrants and approvals and with a diverse number of mechanisms in play. Where do you see the biggest unmet need still persists in NMIBC? How does 002 position to really, you know, unlock those unmet need patient subgroups?
Yeah. I think I would characterize the unmet need in sort of three buckets. I think the first is there is always going to be, until we are at a place where there are zero cystectomies being performed in the United States, there will always be a strong motivation across all stakeholders to, you know, erase the word cystectomy from our vocabulary. As you look at the different mechanisms of action, really what that provides is multiple opportunities, whether it be direct cytotoxic, targeted immunotherapy, or in the case of 002, broad immunopotentiation. You know, there are multiple ways to get at this disease, which is heterogeneous in its nature, but broadly is immunoresponsive. Because it is in the bladder, contained sort of organ system, you can really push dose and sort of treat local disease locally.
As long as patients are, you know, let's assume, you know, just for you and I have done this before, Andres, as a thought experiment, let's imagine that across all mechanisms, modalities, and treatments, everybody at the 12-month time point is able to keep 50% of all treated patients in CR. That means that 50% of any patients started during that year or, you know, 12 months prior will be recurring. They are responsive to therapeutics. What we know is that whatever it was that drove the response to the 12-month time point from a mechanistic perspective is likely not to be repeated. Because we are the only broad-spectrum immunopotentiator in late-stage development, we can follow a targeted immunotherapy. We can follow a chemotherapeutic.
We can be utilized in front of those and not preclude the utilization of those modalities following us because I don't think anybody is going to be at 100% until we get into combination therapies, which is where all oncology settings go. That is a story for another day.
Great. Very helpful. I want to try to move to unpack some of the data that 002 has generated. Let's start first in the BCG unresponsive cohort. Recently reported 67% 12-month CR rate in the pivotal BCG unresponsive cohort as of April. You know, as you look towards the six-month data in the 25 available patients by year-end, what benchmarks should we internally give you the best confidence that it has a best-in-class profile?
I'm reluctant to, with five patients of data, say that.
With the caveat of.
Yeah, yeah. How about best-in-class is sort of in the frame of the art of the possible. Here's how I would break down our unresponsive data. Obviously, we've generated a larger data set in the naive setting, which on the whole is more biologically similar to an unresponsive patient than not, right? We're talking about the same driver mutations. Maybe there's an additional mutation where, you know, they just aren't responsive to a particular signaling pathway. On the whole, that disease is relatively similar. What we've observed in the larger data set of naives is that this long-standing thesis that we've been talking with you and your team about for a while, CIS on its own is a different animal than CIS plus papillary. CIS plus papillary is a more difficult-to-treat disease state. It's two diseases in one.
That should just speak to a higher bar to deliver a complete response. Our unresponsive data set was comprised exclusively of CIS-only patients. There we saw a 100% complete response rate at six months. Utterly unsurprising. CIS is super immunoresponsive. The question that we get, and I think it's a really valid one, and we ask ourselves is, okay, where will those numbers come in? 80%, 100%, 67%? Like, where does that land? You know, we would just look at the dynamics of response in the naives as a, let's say, as an indicator. In the naive setting, we had 58% CIS only and 42% CIS with concomitant papillary. There at the six-month landmark, we were at 80% complete response rate and 50% complete response rate respectively.
I would just note 50% CR in a harder-to-treat population of concomitant papillary is medically meaningful, right, at six months. Let's assume that we wind up, you know, kind of where everybody else is in their registrational or registration design studies in terms of CIS-only enrollment. 75% is kind of what we're targeting. If you took the same delta, 30 percentage points of response between the CIS and the CIS plus papillary, you roll it over to the unresponsives, right, continue to believe that you'll be at 100% in CIS only, and that will comprise 75% of your patients. The algorithm is starting to get complex, I know. All of that would be predictive of a CR rate that is certainly in the 60s, if not in the 70s, which at the end of the day, to answer your question, what does good look like?
It's what our competitors have. CG is at 63% at six months, and we'd be very happy if that's where those numbers came in. Remember, just the arithmetic to get from 100 down to 67 or 63, we have an ample amount of freedom in terms of how many patients can go against us before we start to get it to an irrelevant level. I just don't see that being a part of our story moving forward.
Very helpful. Maybe circling back to a comment on the BCG naive strategy, you know, same disease, but maybe you need to employ a different kind of stance with the FDA. Is there any color you can give us on the potential interactions, what a registrational study could look like, and, you know, a little bit more about the commercial differentiation, specifically in the naive population? As we know, recently we've seen some noise in the space that just because you're approved in one subset doesn't guarantee approval in a secondary. Any high-level thoughts there would be helpful?
Yeah. Let me, your first order consideration in this sort of, let's call it naive, I would like us to start talking about it in terms of BCG eligible, can't get, won't take, don't tolerate BCG, right? Also naive. There we know that the agency requires a randomized controlled study. The question is, what is the standard of care to which you are comparing in that study? We've done an enormous amount of work with claims data to sort of understand, you know, what are those patients who are BCG eligible, be they completely treatment naive or a previous BCG success that is outside of a two-year recurrence window, right? That is a BCG eligible patient that is functionally naive, right? Then there are those that refuse or don't tolerate.
All of those BCG eligible patients, you would have to run a randomized controlled study. BCG is in shortage. BCG is not tolerated in all those patients. It's not, you know, whatever. It's refused in some of those patients. Our objective, and this will unfold over the sort of coming months, is to go to the FDA and show them real-world evidence that suggests that patients who are BCG eligible but can't get, don't want, refuse, don't tolerate, or are truly naive, in many of those cases, gemcitabine, mitomycin, gemdosy, they're actually getting that more than they're getting BCG. That's probably a big function of the shortage, but it's not the only thing.
We'll make the argument that standard of care is not just BCG, but it's, you know, chemotherapeutics as well as BCG, and work with the agency for a trial design that is enrollable and interpretable. You know, that's sort of where we are today. We'll talk more about that as we get feedback from the agency.
Great. And kind of circling back again to some of the key differentiation aspects of 002, you know, you have an up to 80% salvage response in the early data sets. You know, how are you thinking about reinduction strategy in the registrational context? You know, should this be built into the label or, you know, remain a physician-driven decision? Any high-level thoughts there would be helpful.
Yeah. I'll start by saying observationally, all of the patients that we have reinduced in the study, there were no null responders, right? We observed significant sort of regression of CIS disease in all of those patients. It's sort of like they just needed a final little push over the edge. I think that theory they just need a little push is borne out by the fact that we have an 80% salvage rate. At the end of the day, I think about it as a patient or potentially a provider. At the three-month time point, if you can look that patient in the eye and say, "I've had a look and you don't have cancer," that's the win, right? You want to be able to say that.
But in our, because, you know, for instance, our prolonged onset to peak therapeutic effect, the sort of the kinetics of our drug that we've talked about at length, you know, that drives a really well-tolerated safety profile and tolerability profile. At the same time, it's not, you know, dropping a bomb of, you know, inflammation in the bladder the way BCG does. There are trade-offs there. Our view is, you know, as the data set broadens, you know, we're likely to see fewer patients needing reinduction. In that case, if you again can offer that patient at the first look in the bladder, the good news as opposed. Those two, well, there's a little bit left. We're going to go and get that with another course here, right? I think there's like qualitatively that's a better option.
I think, you know, look, in the label, if it says at three months, if there's residual disease, reinduce, I, you know, I don't see it being a part of the label because there are a number of patients who are in CR at three months.
Great. Very helpful. With all of the noisiness that's in the NMIBC space and all the comparators that investors view the competition as, I want you to maybe discuss a little bit of, you know, help us understand, you know, from a urologist perspective, what is the most important features for using the drug they select for NMIBC? Is it, does it fit into my workflow, the safety, kind of order rank those for us to get a better sense of the nuanced differentiation aspects of 002?
The answer is it depends. But let's just like, you have to be clinically relevant, right? You have to be through a threshold of relevance from a response rate, right? I mean, there are a number of aspects to the field of uro-oncology that differentiate it from medical oncology. And we could spend hours talking about what that comprises. I'll try and narrow it down. But at the end of the day, this is cancer. And you want to know that that drug that you're utilizing in that patient is going to be effective, okay? So let's assume that the competitive landscape all sort of reverts to a mean and everybody's in the sixes, sixties at six, and everybody's sort of pushing 50 at 12. You are through a threshold of efficacy.
From there, you have to think about the field as divided between the academic setting and the community setting. Community setting is about 80% of all GU oncologists in the United States. The academic setting would be the remaining 20%. They drive a lot of new product adoption and clinical studies. They have a different series of incentives in the academic setting than in the community. Our view is that our product is easily utilized in all of those settings, but might be really attractive in the community setting. What drives that is I predict that, you know, if you follow the way the conversation has gone in this setting, you know, it's sort of been like, what are six-month numbers? Okay. What are 12-month numbers? What are going to be 24-month numbers? Right?
Once there's nothing left to talk about from that perspective, we start looking at what these products represent to the practice and to the patient. There, the community, it's just like, you know, when you go to the GI doc that is doing a whole lot of colonoscopies, you want those patients in and out and in and out, and you do not want complications, and you do not want calls at 12 in the night saying, "I have gross Hematuria," right? The better tolerated non-practice disruptive administration products, I think, will be very well adopted. Again, got to be through a threshold of relevance in terms of efficacy, but those factors.