Good afternoon, everyone. Thank you for being with us today. Our next presentation is going to be with Protara Therapeutics. I'm joined on stage by Co-founder, Director, and CEO Jesse Shefferman, and Co-founder and Chief Scientific Operations Officer Jackie Zummo. So thank you for being here.
Thank you.
Let's help everybody get on the same page, talk about some background. Your lead program is TARA-002. Can you walk us through this asset and its origin?
Sure. It's got a pretty interesting story, so I'll try and keep it brief. TARA-002 is a genetically distinct strain of Strep pyogenes that was sort of initially bred in sort of a Mendelian fashion to be very low in streptolysin toxicity. It originated in Japan. We have licensed the rights to this asset from Chugai Pharmaceutical, where it was once one of the largest selling oncology products in Japan. Our contention is that it was sort of the first IO drug, only no one had any idea why or how it worked. Very briefly, in the same way that BCG, which if you're in here and you kind of are following the NMIBC story, you know that BCG is also a bacterial therapeutic. This is sort of of the same type, if you will, a broad-spectrum immunopotentiator.
They originally got this product approved to reinvigorate the immune system following its depletion through chemotherapy. But over time, they observed a survival benefit, right? So no idea why or how at that time. And that's, I think, a piece of the story for us. But they eventually got that product approved in lung, gastric, head, neck, and thyroid cancer as adjunctive therapy to chemotherapy. And in fact, that label still exists today. The product in Japan is called Picibanil or OK-432. And the safety database and its utilization in the oncology setting numbers in the tens of thousands. The label in Japan has about 75,000 patients of safety. So that's its origin. We sort of have always viewed ourselves as wanting to be the company that found the next Revlimid. That, to us, is really elegant drug discovery, right?
Taking something with sort of known target, known side effects, but repurposing it for something more relevant, that became a multi-billion-dollar drug. Our hope is that 002 would be the same. So that's sort of the background, and we can talk more about. But we have worldwide rights ex Japan to pursue it in any and all indications. Of course, bacterial therapeutic, immune-activating agent, the breadcrumb trail to NMIBC once we got the rights to this product was pretty obvious.
Super. It's definitely a well-vetted agent. And so you alluded to the bladder cancer space. So your lead program is TARA-002 in non-muscle invasive bladder cancer. Now, that space has multiple players. So let's talk a little bit about what differentiates TARA-002 mechanistically from the competition and what are some of those potential advantages to that.
Sure. So 002 is a broad-spectrum immune potentiator, similar to BCG, but not completely the same. I think what sets it apart is that it definitely what's being investigated right now are mostly broad-spectrum or targeted chemotherapies or targeted immune therapies as well, right? 002, in its broad-spectrum nature, actually hits all of those same sort of cytokines and chemokines that are in the more targeted versions. But it's a broader spectrum immune response. And what that really leads to is durability, long-term durability, which is something that's consistent with BCG.
Excellent. And so you presented some clinical data earlier this year for TARA-002 in non-muscle invasive bladder cancer. What were some of the key learnings from that clinical update?
That was really early data. It was induction only. It was in 16 patients. What we were most encouraged by was the 63% complete response rate in the CIS-only population. I think for us, that's sort of the early dose of data. The data that we have been generating since then is really going to build upon that as we look at the opportunities for this drug in this trial setting to have the advantages of reinduction as well as maintenance treatment.
Absolutely. And so you're currently studying TARA-002 in the phase II ADVANCED-2 trial. Can you talk to us about the study design there?
Sure. So there are two cohorts. The first cohort is the FDA-driven guidance, BCG unresponsive, designed to be registrational study that follows basically what drugs like pembro and Adstiladrin that are approved upon same design. We also have a BCG naive proof of concept study arm that we are enrolling into. And so in total, the study will have 127 patients, 100 in the registrational arm, and then 27 in the proof of concept naive arm.
Relative to the phase I study, which is where we've seen the data previously, how does the design meaningfully differ for the phase II study?
So most importantly, that was just an induction-only trial, right? That was a safety study that we conducted to one confirmed dose and to demonstrate that in a small subset of patients that the drug was safe, FDA requirement for phase I. This study is, again, designed to be registrational in BCG-unresponsive and designed to also give us the opportunity to get a pretty meaningful look at the BCG-naive cohort. The duration is longer. We have reinduction built in, which is something that is unique to, I think, this space in that you can reinduce patients. And we've seen that with other investigational drugs. And so you have the maintenance. So the study is designed to answer all of the questions that the FDA lays out for a sponsor to seek that single-arm study approval in BCG-unresponsive.
With the added ability to do the reinduction, how do you anticipate that will impact the efficacy data that you've seen so far?
So we're encouraged by what we see. And I think when you look at sponsors who have already reported data that are sort of immune potentiating drugs, you can see a pretty meaningful salvage rate. You should expect the same with 002.
We look forward to that. And so you've guided to presenting some more data from that trial later this year. So what specifically would we expect to see at that update?
We had stated that we would be releasing data on at least 10 patients. We're encouraged by the number of patients that we've been able to enroll. We're really focused on the six-month landmark. We'll report CR at any time. But really, when you think about this specific form of cancer, which is chronic and recurrent, you're really looking towards that durability. For us, we're really focused on the six-month landmark data.
Fantastic. And how are you thinking about the benchmark for this high-grade non-muscle invasive bladder cancer setting, just given that there's been an evolving landscape in recent years?
Yeah. So I think we get that question a lot, of course. And we tend to lean on what we hear from investigators, not just KOLs, but folks that are kind of in Dubuque, right? Sort of maybe they see four to five patients a week, something like that. So I think there are two different thresholds in the BCG unresponsive setting, right? The first one, which is lower, would be what's adoptable, right? We've heard from the folks that are out there also with investigational programs as well as people that have approved products. And this is a really big space. Patients do not want their bladders out. They will try everything and anything. And so there's room for lots of players. I think that is a pretty well-rehearsed sort of fact of this particular setting.
So look, I think if you want to be adopted, be an option, third, fourth line, or something like that, I think you've got to be above 50% at six months. Again, we tend to not really emphasize CR at any time because you could be a CR at three months and then fail. And that is as good as a patient who is continuing to be a CR at six, right? They both have the exact same 100% CR at any time. So yeah, I think if you're looking at six-month landmark, you've got to be kind of in the 50s, preferably mid to high. And we've seen what the high watermark thus far is with CG Oncology at 64.8%. And there, that's what I think that's when you go beyond adoptable to embraceable.
What will be the agent that a uro-oncologist reaches for when they see that they have a recurrent CIS patient? If you want to be sort of in the discussion for that first thing that they reach for, you've got to be in the 60s. Alternatively, we are spending a lot of time looking at BCG-naive. Docs love to enroll BCG-naive patients in this study. I think they tend to view it as a BCG replacement. I think we would be happy with BCG alternative in the naive setting. There, your comparator is BCG, but not all the time because BCG is often in shortage, and it has been no matter how many sponsors or manufacturers have supplied the market here in the U.S. anyway, and so BCG is probably in the 70s.
And so if you're going to replace it, you've got to be within sort of 10 points of that, right? So you've got to be in the high 60s, I think, to really just revolutionize that frontline setting. But we know from claims data that there are roughly about 10,000 patients in the United States seeking treatment who would be eligible for BCG but either can't get it or refuse it, right? So that's 10,000 patients. That's most other oncology addressable markets. There, as a BCG alternative, what else is there? And the answer is mitomycin or gemcitabine. And anecdotally, what we hear is that in the CIS high-grade, high-risk setting, gem is the better of the two. And it's probably 45% complete response rate. So you've got to be better than that to be utilized as an alternative, which in its own right is a billion-dollar opportunity.
It is an exciting opportunity. I want to make sure that we have time for your other programs.
Sure.
So let's shift gears a little bit and talk about IV Choline for patients on long-term parenteral support. So talk to us about how this fits into your profile, but as well the unmet medical need for patients on long-term PS.
Yeah. Look, I think we have always kept one foot in oncology and one foot in rare disease. It's a function, really, of the backgrounds that Jackie and I brought to the table when we founded the company. And I think oncology and rare tends to work well together for a number of reasons I won't get into. But there are many, many companies out there that make those two areas their focus. So broadly, choline fits the bill there. And not dissimilar to 002, when we came across the choline asset, it had already done, or in the academic setting, had already completed a phase II study where it demonstrated a pretty significant effect size, right? So if you take a step back, you're looking at two assets that sort of have a degree of de-risking.
You're not looking at a fresh off of the lab kind of science experiment. So that's sort of the background on choline. Kind of what does choline do? So choline is the root substrate for phosphatidylcholine, which is the most ubiquitous phospholipid in the body, right? So any membrane, membrane-like structure, that type of structure would be comprised either of phosphatidylcholine or sphingomyelin. It's ubiquitous. You and I get it in our diets through lecithin, which is sort of the food-based form of it. Parenteral support patients do not get it. They do not get lecithin. And they do not get a sufficient amount of choline in their diet to reliably supply the body with phosphatidylcholine.
On top of the fact that they don't get it, so for some of those patients that maybe aren't on parenteral support every day, many of them lack the absorptive capacity of the small bowel to actually absorb choline. So in many ways, while this is a function of perhaps a surgery or downstream from some other type of disease like Crohn's or something like that, this very much is like an inborn error of a substrate kind of manufacturing. And so it really does fit the bill of the body doesn't have this compound. It can't get it, can't absorb it. We replace it. And Jackie will talk you through some work that we did to ensure that these patients actually are choline deficient. There's an enormous body of literature that suggests that choline deficiency in vertebrates inevitably results in multiple different sequelae.
For males, it's mostly liver dysfunction because obviously, there's a lot of phospholipid activity in the liver. So that's it. There are about 26,000 patients in the United States who are on long-term parenteral nutrition who would be eligible for choline replacement therapy. I mean, if you think about that, that is among the very largest of kind of rare disease opportunities for which there are either drugs in development or drugs that have been developed. So it's a real big opportunity. And we'll talk a little bit about what is a fairly straightforward regulatory path and some of the data that suggests that these patients need this type of replacement therapy.
Yeah, absolutely. And you're alluding to the THRIVE-1 study. Why don't you tell us some of the key clinical learnings from that?
Sure. The THRIVE-1 study was conducted globally. What we looked at there was we wanted to make sure that in parenteral support patients, they were choline deficient. We found that approximately 80% of patients that are on long-term parenteral support are, in fact, choline deficient. What was even more, I think, striking and interesting is that of those, about 65% of those patients had some form of liver dysfunction. It just goes to really underscoring what Jesse said about the long-term sort of sequelae that happens when you have a choline deficiency.
Absolutely. Well, there's certainly a need and an opportunity there. And I know you guys are preparing to initiate your pivotal phase II-B/III THRIVE-3 trials shortly. So talk to us about the trial design there.
Sure. So it's a II-B/III seamless design study. In the first II-B component of it, we'll do a dose confirmation assessment in 24 patients. It's an eight-week endpoint looking at the elevation of choline levels in that patient population. That is also then the primary endpoint in our randomized controlled trial that will be controlled against placebo. There, we're looking at a 24-week endpoint. And again, the endpoint is a PK endpoint looking at elevation of choline levels in this patient population.
Perfect. And what is the expected timeline to receive the initial data on that trial?
We'll be looking probably at the II-B data in the second half of 2025, followed then with about an 18-month overall recruitment period for the whole study to then get to the endpoint in the RCT.
OK, fantastic. And you guys were recently granted a Fast Track designation by the FDA for this program. So talk to us about the significance of that designation as well as how that affects your timeline to potential filing?
Sure. So I mean, fast-track designation is really a nod from the FDA that demonstrates that this is truly an unmet need and that this drug has the opportunity to fill that unmet need. I think that for us, it really signals the agency's alignment with us that we think that this is a meaningful treatment for this patient population for which there is no other treatment for choline deficiency. What it means from a regulatory filing perspective is that we do get a rolling filing of our NDA. In addition to that, it gives us access to key members of our clinical review team throughout the process. And we've been really lucky to have an ongoing dialogue with our clinical team that have been really helpful in helping us to streamline a regulatory path to get this drug to market as soon as possible for these patients.
Yes. I know we're all certainly looking forward to that. Let's move back to TARA-002, but in the other indication in which you're studying it, which is lymphatic malformations. So talk to us about the market opportunity there and how you're thinking about the LM subtypes, including macrocystic, microcystic, and mixed cystic.
Sure. As a background, lymphatic malformations are structural malformations of the lymphatic system driven by sort of somatic genetic mutations in the AKT, PI3K, and mTOR pathway. They typically show up in utero. This is absolutely a pediatric setting. The epi is a little funky. There are about 2,000 live births per year in the United States. No standard of care here. Standard of care would be surgery or sort of bleomycin, which can turn your teeth brown. Because the lymphatic system is so sort of prevalent up in the head and neck area, this is where these malformations tend to sort of manifest. Look, it's significantly disfiguring. It carries a lot of sort of health risk along with it, airway blockage. It's got a low mortality rate, but it has a very, very high morbidity rate.
I think for those of you who are parents in the room, having a child that has a significant disfigurement, thinking about going into school and being in that environment, there's a high urgency of treatment both among patients and parents. Prevalence is tough to nail down. We sort of think there's roughly 27,000 patients living with lymphatic malformations. We also want to be a little circumspect about that because if you think about it, if you have lived with a malformation, you may not have that same urgency to treatment as a pediatric kid. So when we talk about chipping away at that prevalence pool to comprise what is our true opportunity, we want to be kind of sanguine about how much of that we're going to capture. But we do believe that TARA-002 certainly will be the only approved product for macrocystic.
You alluded to this. These manifest as macrocystic. So that's a balloon. That's a big, round structure filled with lymphatic fluid. And this is where TARA-002 works really, really well. We drain the malformation and then re-inject TARA-002, same sort of volume of fluid removed and saline. And this is the standard of care in Japan. It's still used in every single lymphatic malformations case for which it's appropriate in Japan. So macrocystic or mixed, which is sort of macro, micro. Micro is more fleshy with less internal space. That's not going to work for us. Our drug has to be injected and be able to reach all of the aberrant cells in order to really drive change there. We know that our colleagues at Relay and our colleagues at Palvella are looking at microcystic. And I think that that's a great opportunity for those kids.
This drug has been used in microcystic, and it's about a 20% complete response rate versus the last study that conducted with OK-432, again, the same exact drug, about an 80% complete or substantial response rate in macrocystic kids. We also have seen some results of the initial patients in the study that sort of underpin that efficacy.
That's right. So TARA-002 is being studied in LM in the phase II STARBORN-1 trial at this time. Can you talk to us about the study design and what special considerations you've made given the pediatric population that you're studying?
Sure. So there's three. So we're trying to study from six months to 17 years, right, the entire spectrum of pediatric patients. And so you want to do that very responsibly. So we started with three safety sentinels looking at six to 17-year-olds and then dropping down to two to six-year-olds and then really going down to that six-month to two-year-olds. We have completed the first safety sentinel. We had really great results of the three patients, two of them at a complete response or substantial response after a single dose of 002. So it just speaks to the effect that this drug can have in the right type of cyst. We're now moving on to the lower ages. And we're really encouraged by what we're seeing across our sites in terms of the number of patients that are really looking to be treated with this.
I mean, our safety slots are all full, and we're hoping to move faster now that we're into the lower age groups.
Super. And so I know you talked about the cohort one results were promising. And you're in cohort two now. So what are we thinking about in terms of the timeline to get some readout from those?
It's challenging to really pinpoint that. The reason why is because the first cohort enrolled and they had a complete response after a single dose. It could be up to four doses that are required. It could be anywhere from six weeks to eight months for a cohort to complete. We are hopeful, just given where we are from a recruitment perspective and enrollment perspective, that we'll see data in the first half of 2025. It could creep into the end of 2025, just given that range of potential dosing required.
Yeah. I can tell you that we have germane to kind of how I was describing urgency to treat. And it's sort of a family decision, as is the case with all kind of rare pediatric diseases. We've had a backlog of patients wanting to join the study for several months now. And I think that, again, that's good for us in terms of being able to get through the next safety sentinels and the broader efficacy population. But it also helps when it comes time to have regulatory discussions, right? We benefit from that same sort of enthusiasm and connectivity with families and the physicians that tends to drive positive results when you go in front of the FDA for things like, hey, would this qualify for accelerated approval, right? It's a biomarker endpoint imaging. And it's in a pediatric population for which there's no alternative approved treatment.
We need to be careful when we talk about kind of regulatory ease because paradoxically, we are in the vaccines division, and vaccines just doesn't have that breadth of experience in working with rare pediatric diseases. They did grant us rare pediatric disease designation, so upon approval, we would get a PRV. But we are educating them not only on the drug itself but on the disease and, in some respects, rare disease regulatory processes.
Perfect. Well, I think we're up on time. But thank you so much for being here. And thank you all for attending.
Thanks, everybody.
Great.