Good morning. I'm Charles Zhu, one of the Senior Biotechnology Analysts here at Guggenheim Securities. For our next session, we are joined by Protara, specifically Jackie and Jathin from Protara. I wanna thank you very much for your participation at our conference today. Perhaps just to kick us off, could you provide us with a brief overview of your company platform and pipeline, please?
Sure. Thanks for having us here today. Protara is a New York City-based biopharm company. We take the approach of providing advanced scientific approaches to establish mechanisms. Our lead program is TARA-002. We are initially looking at that in non-muscle invasive bladder cancer. TARA-002 is a immunopotentiator that we are also looking at it in the rare pediatric disease, lymphatic malformations. We have a third program, IV Choline Chloride, which is for a rare liver disease, intestinal failure-associated liver disease that occurs in patients who are dependent on parenteral nutrition. We have a very strong balance sheet, and we're excited to talk to you today about our programs.
Perfect. Great. Perhaps, you know, on your program, TARA-002, could you perhaps provide us with, you know, also an overview of the mechanism of action as well as the history of this asset, and, you know, your rationale for pursuing non-muscle invasive bladder cancer?
Sure. I'll take it in a little bit different order than what you just said, but to start with, you know, why 002? 002 is based on OK-432, which is the predecessor drug that is approved currently in Japan. In Japan, it is approved for five different oncology indications as well as for lymphatic malformations. Our understanding of this drug in terms of its mechanism is that it is an immunopotentiator, that it basically elicits the innate immune system to release a wide range of cytokines that then are very much associated with the Th1 immune response. That's our understanding of it. Why non-muscle invasive bladder cancer?
In the literature, you can find several publications on about 150 patients where OK-432, the predecessor compound, was used and demonstrated very clinically meaningful efficacy as well as a very reasonable safety profile. For us, that gave us human data to be able to base our thesis on in combination also with the fact that it is approved in multiple oncology indications.
Perfect. Great. Can you perhaps also provide a little bit more color around your thoughts on derisking data? You know, could you also remind us of the doses evaluated in those historical studies relative to what you're evaluating in the clinic?
Sure. I'll leave that to you, Jathin.
Yeah. We have the privilege of being able to look at over 2,000 publications in the human literature, and that includes the five indications that OK-432 is approved in Japan, but also includes a multitude of others, and one of those is non-muscle invasive bladder cancer. There is about 135 patients that were dosed intravesically, and the doses ranged from the Japanese label, which was 1 Klinische Einheit, which means clinical unit in German. I understand it's a Japanese drug, German unit. We're not gonna go there. The standard dose is 1 Klinische Einheit, and it went up to a maximum of 10, and that's actually how we anchored our phase Ia study that I'm sure we're gonna talk about momentarily.
It's one example of how we can do smarter clinical development using the existing human literature.
Great. Regarding your phase I for NMIBC, it looks like you've guided to an update in the H1 of 2022. Could you perhaps remind us of the trial design or sometime later this year? Could you remind us of the trial design as well as how you're setting expectations for that readout?
We did change the route of administration. OK-432 in Japan was through a variety of routes, including IV, subQ, intramuscular. When you go intravesical, we changed the route of administration, so we opened a new IND to do that, and we have to do a phase Ia dose escalation design. It's a standard 3+3, and it enrolls patients that have either papillary TA disease or CIS disease. Those are treated differently from a regulatory standpoint. They're considered different labels, we're allowing all of those patients to come into the study so we can dose them from a safety standpoint, even analyze them on preliminary efficacy.
Great. What should investors expect in terms of, you know, preliminary, you know, data and what the types and as well as quantity of data from your first readout?
Yeah. We press released last March that we dosed our first patient, and typically accrual rates tend to go up after that, so we've been very pleased with accrual. You can expect safety data first and foremost because it is a safety trial. That's the regulatory purpose of it. From an efficacy standpoint, it'll depend on the types of populations that enroll. Papillary disease tends to be the more common, but if we were to enroll CIS patients, we'd be able to look at those bladders as well. The important point is this is a seamless design, so it rolls into a Phase Ib, in which case we've narrowed the population to just CIS, which is the easiest to evaluate, and we're enrolling up to 12 patients in that cohort to give us further efficacy data.
When we release it will depend and how we release it depends on kind of the blend of those two programs.
Great. Once you've identified a go-forward dose, how do you imagine developing TARA-002 within the NMIBC treatment landscape, and how do you think about next development steps and, you know, potentially longer-term the path to registration?
NMIBC, one of the reasons we're out here is because NMIBC is a highly unusual disease, and it's a little bit nuanced. The endpoints are nuanced. It's a composite endpoint, so unlike other oncology where you're doing a CAT scan, you're actually looking at a composite of cystoscopic evaluations. Also the regulatory pathway is a little bit unusual. You have this situation where in the 2018 FDA guidance, the FDA has indicated you can, in the BCG-unresponsive setting, do a single-arm open label registrational study. That's highly unusual in oncology. That's one avenue. The other is in the, you know, in this phase Ib, we are looking at all different types of exposures.
You can be BCG-unresponsive, you can be less than adequate exposed, or you could be naïve, and we'd be looking at avenues to do that in those domains as well. Multiple opportunities, but if you were to stick to the strict guidance, the clearest and cleanest defined opportunity would be in the BCG-unresponsive CIS space.
Great. How should we think about potential clinical as well as regulatory benchmarks in each of these respective settings, not only in BCG-naïve but also BCG-unresponsive or pre-treated?
Yeah. I should reiterate that I am a practicing urologic oncologist, and my community is really excited for the possibility of having a therapy that's available, underscore to available. The first thing would be clinically meaningful would be that the drug has to be available. In terms of efficacy, you know, we would look towards multiple benchmarks. Out there is intravesical chemotherapies. In the naive settings, they can be around 35%. There's also BCG in the naive setting. That response rate is around 50%. We believe that if you are an immunotherapy that behaves like a bacteria rather than chemo, we would shoot for the realm of 50%.
Great. How should we also think about, you know, your potential competitive positioning relative to some of the other therapies that have also emerged in this particular disease?
Yeah. The word is getting out about NMIBC, so you're seeing some other competitors in the landscape. There are different approaches. There's adenoviral vectors, which are very different than ours. One of the elements of adenoviruses is that you can develop anti-drug antibodies and have a very decreased durability of your response. That doesn't seem to be the case with bacterial therapeutics because it's a little bit different. People are trying combination therapies as a part of the landscape. What I should mention is that nothing that we're doing is mutually exclusive for any of those things. We'll dance with anyone, but it's important to have a monotherapy strategy first. We're investigating these as monotherapies first, and then we'll go from there.
Great. Also, you know, like how should we think about, you know, the risk of a recurrence for these patients on any sort of therapies, whether it's intravesical chemo or BCG or any of the emerging ones and, you know, how does that potentially impact, for example, the market opportunity for NMIBC?
Yeah. I'll speak from my personal practice. When a patient fails therapy, they get their bladders removed, and there's a very significant diminishment in their quality of life. It's not a trivial surgery for a lot of my patients that I perform cystectomies on. I tell them it's the biggest surgery they'll ever have in their life, and that's true. In an elderly population, your 90-day mortality rate is 4%. You typically have an ostomy to drain your urine rather than through your native urethra, so there's a major adjustment there. There's in terms of sexual performance, there's a diminishment of that as well. These are not trivial things, and it's things patients take very seriously.
My belief is that patients would be willing to go through first line, second line, third line, fourth line, as many lines as you need to preserve bladders. The key here is that Protara is in the game of saving bladders, and how we do that and how we approach that is, you know, we'll have to be creative. But we just disclosed a monotherapy program to do that. That's the take-home point, is that losing your bladder is not trivial at all, and that's kind of the key focus here.
Got it. Given that significant impact to quality of life, what are perhaps your views on a potential re-challenge with the same therapy, you know, potentially with TARA-002?
Sure. Yeah. One of the unusual things about bacterial therapeutics is that you can do re-challenges after your first treatment failure, okay? If you are a CIS patient, for example, who failed therapy after the first six doses, you have the potential to get six more doses to salvage that, which is huge because you could salvage losing your bladder. That's a major therapeutic benefit to patients. That seems to be more common with bacterial therapeutics, which we are, so that's what we're considering. That would be, that's starting to become the modern endpoint in CIS these days.
Great. Also, you know, in addition to some of these emerging intravesical therapies, we also have systemic therapies, you know, that first entered the metastatic setting and are now moving their way earlier and earlier. How do you see TARA-002 as well as intravesical therapies in general being positioned relative to systemically administered therapies?
I mean, it's kind of interesting seeing how systemic therapies were developed versus intravesical therapies were developed. The systemic therapies start late line and march backwards. Intravesical therapies can sometimes march in the different direction. Where they converge is where things get very interesting for combination therapies. As a monotherapy-IV systemic therapies have been extremely limited in terms of their adoption because a urologist clinic is not always set up that way. We are very comfortable with administering intravesical agents, but we don't have infusion centers. We're not medical oncologists who treat advanced and metastatic disease very often. You'd have to drive across town to get that therapy and then come back to me to get your efficacy analyses.
If your response rates are below, let's just say 50%, it becomes very hard to adopt that type of a regimen. I think there's some opportunity in the combination settings if you can really knock it out of the park in efficacy. As a monotherapy, those types of things have been limited. Suffice it to say, the route of administration that we're pursuing is urologist top choice, and you can look at any survey. Their preference is certainly to do an intravesical therapy.
Great. I also want to follow up on one of those comments that you made, you know, specifically being that, you know, intravesical therapies tend to start on one end and go down in the other direction relative to systemic therapy. I guess in line with that, you know, what are your views on potential longer-term opportunities, let's say in muscle-invasive disease, for example, or even more advanced settings?
Yeah. Any disease that exists in the bladder before its removal is fair game for an intravesical therapy. That can be low-grade disease, low-grade intermediate disease, risk disease. In the high-risk space it can be BCG-naïve, it can be BCG-unresponsive, and even in muscle-invasive bladder cancer, there is a period of time before the bladder is removed in which you can administer an intravesical agent. You know, we have many opportunities ahead of us within NMIBC and even MIBC.
Great. Also, you know, like, how should we also think about, you know, maybe zooming out a bit, you know, the BCG shortage and how that kind of impacts your thinking around standard of care? Is this something that, you know, could be resolved sometime in the near future, or how do you think about that?
Our company's perspective, and I'll ask Jackie to chime in on some of our manufacturing advantages, but because it really does tie into that. Our perspective is that BCG has been... and this is an outsider's view, okay? We don't work for any of the BCG companies. Has been that BCG is a very difficult drug to make, okay? The reason I say that is 'cause we are now in the 10th year of our shortage, and it's been pretty much continuous. We've had three strains of BCG in the United States, and all of them have gone into shortage. The doubling time is about 16 hours.
Mm-hmm.
That's one of the reasons why you can't culture Mycobacterium when you're suspecting a TB infection, 'cause it's not culturable, which means it's hard to grow. You can have a lot of batch failures. When you combine all of those, every strain of BCG in the United States has had some form of a shortage or another. Even in the context of clinical trials, there have been those types of shortages. Now, what we did is we took this drug from Japan, modernized its manufacturing, and it happens to be a Streptococcus pyogenes that has certain advantages, and I'll kinda pass that mic over to Jackie.
I mean, just starting with the doubling time, our doubling time is about two hours, much quicker. In addition to that, the way that we manufacture this drug in terms of its media, in terms of sterilization processes, we just have advantages over BCG in pretty much every step of the way. We've produced tens of thousands of vials at this point with no failed batches. We're very confident in our manufacturing capabilities, you know, the way that we've built our manufacturing facility, it's in such a way that we will be able to meet demand across the board for all of the different, various forms of NMIBC.
Great. Also given that, you know, you took this therapy over from Japan and it has been available in Japan for quite a while now, how should investors think about, you know, IP runway as well as protection of exclusivity?
Right off the bat, upon approval, we'll have 12 years of biologics exclusivity. In addition to that, the master cell bank is very key to being able to make this drug, and right now it's just us and Chugai who actually have that. Without it's very difficult to manufacture this. In addition to that, it's really about the end process and release and the way in which we manufacture that gives us confidence that it's quite challenging without the know-how to be able to produce this. We will of course, pursue as much IP as we can as we move through new indications, as we think about how we have formulated this, and that's something that we'll always be focused on, and we're confident that through the years we'll be able to establish additional IP around what we already know is standard.
Maybe I can share a little bit, a story with you about how we got the asset and brought it over that kind of ties into this, and it really follows along the themes of why we believe we're so de-risked. Not only do we have the human literature that we can reference, but we're actually re- de-risked from a manufacturing standpoint. When we did this deal with Chugai, the key component was that we would modernize the manufacturing and perfect that technique in the United States. We believe the risk is decreased where you're going to run into Module 3 problems, which is the manufacturing component of your BLA submission, relative to somebody else who's kind of starting from scratch, has to build these small batches of drug and kind of scale up commercially. We already have the majority of those capacities.
Right. Yeah, we're producing at commercial scale now.
Great. Great. I know that, you know, the focus has been purely or mostly on, you know, bladder cancer, but I also wanna touch upon lymphatic malformations. I believe you mentioned it was OK-432 was already approved in Japan for this disease. You know, how do you think about the opportunity here as well as your activities and potential next development steps?
It is the standard of care in Japan. We're very excited about our opportunities here in the US. We're just on the beginning phases of starting our phase II study. We're very excited about it. A lot of our sites are those that were involved in the Compassionate Use Program that was available here in the US. There's a lot of excitement around the PIs that treat these children. This is a disease that primarily occurs in children under the age of three. There's no FDA-approved products at this time. We're very excited to be able to get this program underway. We think it's gonna mean a lot for these patients and their families.
Got it. How would you characterize as well the potential total addressable market for lymphatic malformation, perhaps also for non-muscle invasive bladder cancer?
Yeah. I'll start with LMs and then let Jathin speak to NMIBC. You know, the literature and epi is a little bit all over the place, but you can think about it anywhere from around 1,400-1,800 patients in the U.S., and, you know, like I said, with no approved products, we think we'd be able to capture a significant number of those patients.
In NMIBC, if you were to ask a Uro-oncologist, which of your three key... We have three main diseases, prostate cancer, kidney cancer, and bladder cancer. Which of those three causes you the most burnout? I think you would unequivocally get the answer of bladder cancer. There's a lot of bladder cancer out there. It's the number 6 most common cancer. About 80% of it is non-muscle invasive disease, which is managed primarily by the urologist, and on top of that, it has approximately a five-year 50% recurrence rate. You have to deal with not only the incident bladder cancer, which is the numbers I just quoted you, but also the prevalent population that's due to recur. That's the source of the urologist burnout, but it's also the market opportunity for Protara.
Yeah.
Great. Great. Perhaps, just to close on our last couple of minutes here, could you also remind us of your current cash balance, cash runway, and how that stacks up relative to your upcoming near term, you know, milestones and potential catalysts?
Sure. Currently, we have about $107 million on the balance sheet. We're guiding that that will take us through the second half of 2024. Along the way, we believe that we're going to be able to generate meaningful catalysts both in the non-muscle invasive bladder cancer program, and we hope to also be able to do that in LMs.
Perfect. Great. With that, Jackie and Jathin, I wanted to thank you again for your time as well as your participation in our conference. I hope you have a nice rest of your day.
Thank you.
Thank you.
Okay.