Am I muted? Okay. Well, thanks so much for joining our 46th Annual Healthcare Conference. I'm Stacy Ku, part of the biotech team with my colleague Vishwesh Shah. We'd love to welcome the Protara team, Jesse Shefferman, CEO, Jackie Zummo, Co-founder and Chief Scientific Officer, Patrick Fabbio, CFO, and Justine O'Malley, Head of IR. Thank you so much for joining. There's just so much investor interest these days in NMIBC, and we're very excited to be discussing TARA-002-
Mm-hmm
... recent and upcoming updates. Just as a quick introduction, can you provide some background on your lead program, TARA-002?
Yeah.
When I say brief, we'll probably dig into a lot.
Yeah
... of the recent data.
You're-
So-
You're playing with fire asking me to be brief.
Step by step.
Okay. Yeah, TARA-002 is one of two bacterial therapeutics either sort of in clinical studies or approved, the other being BCG. What that means is it's a whole cell bacteria that through our manufacturing process, we engineer to a state of inactivation versus attenuation.
What that does is it conveys and retains all of the antigens that, you know, drive a host immune response while also conveying none of the toxicities associated with streptolysin or Streptococcus pyogenes exotoxin. You're basically, you know, sort of duping the immune system into launching a really well-conserved, you know, broad spectrum immune response to a pathogen that is really just a ghost, for lack of a better term.
It was originally developed by Chugai Pharmaceutical in the 1970s as adjunctive therapy to chemotherapy, the purpose there was to sort of reinvigorate the immune system following a massively immunodepleted chemotherapeutic regimen.
Over time, they observed survival benefit, ultimately, this product at that time, you know, under Chugai's ownership was called OK-432. Over time, more than 65,000 patients were treated in Japan for head, neck, and thyroid, gastric and lung cancer using this compound, OK-432, adjunctively to chemotherapy, in all of those cases, the Kaplan-Meier curve separated and stayed separate for a long time.
There's this massive efficacy experience, this massive safety experience, and we've now taken this sort of what we believe is probably the first ever marketed immune oncology agent, modernized our understanding of it, because think about how much the field of IO and just even the assays that we utilize to understand that activity, it's grown by leaps and bounds.
It allows us to look at this OK-432, and again, it's literally the same drug, same master cell bank, same manufacturing process, but, you know, modernized in certain places. It allows us to look at this from a very modern lens. Going back to the fact that the standard of care in NMIBC is the only other bacterial therapeutic out there, it seemed like a very natural fit when we acquired the rights.
We're prosecuting, you know, a fairly broad NMIBC program in both BCG-unresponsive, carcinoma in situ patients, as well as, on the horizon, a randomized controlled study of OO2 in sort of a frontline plus an exposed, BCG exposed setting for which there's really, you know, these patients sort of fall into a donut hole. Also the lymphatic malformations program, where OK-432 is still used and is the standard of care in Japan, and several hundred kids every year are treated successfully with this product.
Okay. Wonderful.
Is that brief enough?
A wonderful overview. Just last week, we provided a key update.
Yes.
You all provided a key update.
Mm-hmm
... in the BCG-unresponsive patient population for NMIBC, and obviously an update for BCG-naive, which we'll get to.
Sure.
If we could just start with the six-month data.
Mm-hmm.
help us benchmark your current efficacy versus the competitive landscape.
Yeah. you know, there are two sort of six-month measures that are kind of used interchangeably. I think one is infinitely more important than the other. there's CR at any time at the six-month time point.
Yeah.
That is the canonical primary approvable endpoint for all of these single-arm open label studies that have been conducted by CG Oncology and J&J and Merck, right? We're conducting that same study with ADVANCED-2. There, there's the CR at any time piece, but you can be a non-responder at three months and then be re-induced and be a responder at six months, or you can be a responder at three months and then progress at six.
Both of those patients have a 100% CR at any time. We tend to look at landmark six-month CR, which is the patient cancer-free at six months? There, we've published the highest number of anybody out there, both in development and approved, at 68% CR at six months, and we're very proud of that. Our CR at any time is 65%, which, you know, it's always going to incorporate a three-month evaluable patient that's not yet six.
Okay. Again, our view of the KOL feedback is for them to use another agent ahead of cystectomy. You clearly have exceeded that hurdle.
Yeah.
Again, although we view the data as quite immature.
Mm-hmm
... you all also disclosed 12-month data as well.
Yeah.
So-
Yeah
just help us understand, maybe level set the efficacy that's been disclosed so far.
Sure.
Talk about your conviction around why you believe that efficacy rate.
Yeah
... continue to improve over time.
I think it's important to contextualize three different groups of stakeholders that we have an obligation to. I think the first, obviously, are the providers and patients, who are seeking novel treatments in an increasingly complex and hard to follow landscape. You know, OO2, as the only broad-spectrum immunopotentiator, not targeted immunotherapy, not, you know, enhanced chemo, it offers a very compelling alternative MOA, and we can get into sort of the ease of use and tolerability, which are among the very, very best of any sort of investigational therapeutic.
Those physicians, we've just come back from GU ASCO, and just to give everybody a sense, we published in five out of 15 patients were in CR at the 12-month time point, which is a 33% 12-month CR rate.
The first thing that I would say is for that stakeholder group, 33% is a therapeutically meaningful number. That is not the only stakeholder out there that is looking at 12-month data. Our other stakeholder that we really care about, because at the end of the day, we're playing for the approval and not the podium, is the FDA. The FDA, to be clear, our primary approvable endpoint is CR at any time at the 6-month time point. We're clearly over a hurdle of approvability there. The durability measure that FDA actually cares about is DOR. 12-month landmark is not a product of sort of a regulatory pathway.
One of our competitors published a 12-month landmark number in sort of the 46% range. All of a sudden the world is like, "That's the measure of an adoptable, efficacious, reimbursable NMIBC product." I'm a little bitter about that, because the reality is that in order for us to get approved, what we need to show is DOR. These data are too immature to demonstrate DOR. Finally, there are the investors that have underwritten this incredible opportunity to take this drug and reimagine it. There it is so very hard to contextualize one response rate versus another. You know, it's you can have a mandatory biopsy at three months like we do.
In fact, we're the only ones that have a mandatory biopsy at three months, and you're gonna have a much lower three-month response rate than anybody else because you're capturing microscopic disease 'cause you're puncturing the bladder all over the place. That, these are all heterogeneously conducted studies.
To cut to the chase, I think the world wants us to show a 12-month landmark CR that starts with a four. Here's what I'll tell you. Coming into the GU ASCO data, when our N was 13, we had a four handle on our 12-month landmark number. We had two patients go against us in the matter of a week. The first patient was a three-month failure, a progressor.
It's the worst thing to happen to a landmark assessment of response at a low N, because that three-month failure goes directly to your denominator while your three-month CRs, six-month CRs, nine-month CRs do not. How we contextualize it, we would never make a decision strategically on the first 15 patients of a 100-patient study.
Secondly, 33% gives us a very comfortable, what I would say is sort of, floor off of which to see those numbers improve. I won't go into, like, a swim lane by swim lane analysis, but suffice it to say that there are enough three months, six months, and nine-month responders in that Swimmer plot that we published recently that you can see that number getting up to 40.
What I would say is this: If those 2 patients had gone our way and moved our landmark CR above 50%, best in class, would we have gotten credit? Would the world have said, "That's the best possible CR at 12 months"? They would say no, because it's only 15 patients. Our job is to continue enrollment, to continue to treat patients, and to continue to evaluate these data as they mature, knowing that a approved product in BCG-unresponsive CIS is not a billion-dollar drug. It's not for us, it's not for J&J or CG or Actavis. Nobody is making $1 billion a year in peak revenues off of carcinoma in situ BCG-unresponsive patients.
For us, where the real significant and meaty revenue opportunity lives is in this unique frontline, sort of BCG alternative, frontline plus, and potentially BCG exposed patient population, which numbers north of 20,000 in totality of addressable patients. Our objective is, as is the case for all the sponsors in the NMIBC setting, the single arm open label BCG unresponsive CIS study that the FDA has allowed us all to do is the fastest path to registration.
Get your drug approved, get on the market, get J-codes, get billing in place, get volume discounts in place with your group urology practices. Use that approval to sort of prepare the market for what will inevitably come 12 months later, which is the likely and hopeful approval of the ADVANCED-2 study in that frontline plus exposed population.
As we think about, enrollment for the BCG-unresponsive patient population, sounds like you've got it to second half.
Yeah. I would say full enrollment comfortably in the second half of this year.
As we think about the BCG-naive opportunity.
Mm.
remind us the data, the most updated data that's been.
Yeah
... disclosed so far and of course, segue into the phase 3 design.
Thank you. We in 31 evaluable patients have demonstrated a 72% CR at any time, a 68% CR at 6 months, and a 58% CR at 12 months. Just to, again, to go back to this 12-month, that number when we first published was 43%, and as the N grew, it became 53%, and as the N grew, it's now at 58%. We're basically at pretty much complete enrollment, and there's not very many more patients. The ultimate N for the naives at 12 months will be 19 patients, of course, we're quite close to that.
It feels like that number settles out in that high fifties range, which is fantastic if you're thinking about providing an alternative, an immunologic alternative to BCG when BCG is either not appropriate for a patient, intolerant, patients are intolerant, refuse, or can't get access to.
talk about the phase 3 design.
Yeah.
Obviously, you've gotten some unique FDA feedback?
Yeah.
Let's walk through those different nuances.
The team, who is sitting here, including one of our board members, by the way, I gotta be on my best behavior. We looked at claims analysis from Optum, which historically FDA has sorta said, "Yeah, that we buy whatever it is that that real world data suggests." We looked at seven years of claims data of NMIBC patients that do not have the code for refractoriness to BCG.
Ergo, irrespective of whether it's recurrence or it's a newly incident case, it's a BCG-eligible patient. What we observed over that seven-year period is anywhere from 11,000 patients - 15,000 patients annually don't get BCG despite the fact that they would, by code, be eligible for BCG.
As we looked at that patient-level data, what we observed was about 50% of those patients got gemcitabine monotherapy, about 38% of those patients got mitomycin monotherapy, about 10%-11% got Gem/Doce, then the rest was some combination of valrubicin or other investigational products.
What that said to us is that that's like a 5x the size of BCG-unresponsive CIS opportunity to slot in, not as a competitor to BCG, but as an alternative to BCG. Of course, for patients that are BCG exposed, which is really inadequately treated, that's another 10,000 patients on top of that. We're still in dialogue about including exposed patients, but where we have alignment with FDA is on that first piece. Can't get, doesn't tolerate, refuses, or otherwise, you know, BCG is inappropriate.
What the Agency saw was, "Wow, that is a significant unmet need." So we agreed on sort of, I think, three really critical pieces. The first, it'll be an R-RCT, so one of, kind of the handful of RCTs conducted in the NMIBC setting, which obviously gives you level 1 evidence, helps you downstream with reimbursement and guidelines.
The Agency allowed us to compare to investigator's choice of either gem mono or mitomycin mono. There, just to give everybody a sense, the claim suggests that gem is somewhere at six months between sort of 45%-50%. You should expect in a well-controlled trial that it'll do better. Then mito is sort of 38%, 40% at 6 months. Then at 12 months, gem's around 14%, 15%, and mito is typically not durable to 12 months.
If you think about the numbers I just laid out for you, 68% at six and 58% at 12, it feels, you know, all else held equal, like we're in a good spot. The N in that study, we've stated publicly is 500 patients total. I think we're comfortably south of 500 patients. Most importantly is the endpoint, right? I think a lot of folks thought that we would have to do sort of like an EFS or RFS type endpoint.
The agency agreed that in the CIS population that doesn't get, doesn't tolerate, et cetera, the approvable endpoint would be landmark CR at six months, not CR at any time. Because we have reinduction, that helps us with, you know, with our landmark six-month CR as well as our, I guess, our at any time.
Again, DOR, 12-month, at the 12-month time point, what's your durability of response? That's a winnable study. It is not a you're in the clinic forever doing sort of an EFS type endpoint. It's six and 12, fewer than 500 patients with, we think, a winnable comparator. Hats off to my co-founder, Jackie. Creative, always has gotten us creative wins with the FDA, and this one, I think, stands at the very top of the pile there.
Okay. Wonderful. Do you have a range as it relates to the BCG-exposed population in this 500...
Yeah
... patient study?
What I can tell you is that we are in active dialogue with the agency. What I'm comfortable saying is that they very much understand. By the way, you can go to the August 2024 guidance from FDA on NMIBC to kind of see where this teases out. They're comfortable saying that exposed is an appropriate population to include in our definition of the, you know, enrollable population.
Okay. Understood. It sounds like you're guiding for initiation of the study in the second half this year.
Listen, we're doing feasibility as we speak. We're looking at 100 sites. Our CRO is identifying sites. The good news is, you know, as is the case, you know, it took us longer than we had hoped, I think, to enroll ADVANCED-2, but now we've got two, in some cases, three years of experience with sites, and so now you show them this ADVANCED-3 study, which is, hey, you know, here's your alternative to BCG. There's a lot of enthusiasm. Just as a reminder, we enroll five in cohort A and B of ADVANCED-2. We enroll five naives for every one unresponsive.
Yep. We were gonna ask about that. From what we recall, it was much faster-
Yeah
for the BCG naive setting.
Yeah.
Okay. Understood. Before we get to maybe the big picture opportunity…
Mm-hmm
... for TARA-002 and NMIBC, and we think about next catalysts.
Mm-hmm
... when would the next twelve-month fulsome data come for the BCG-unresponsive population?
Listen, we put out what we deemed to be immature 12-month data last week because we felt we had an obligation to investors, right? I think the last thing you wanna do is sort of hide the ball. You wanna be scientifically rigorous and say, "This is where the data sits today." You can agree or not agree that it's immature, but we're sitting in a moment right now with this NMIBC program where we are not obligated to publish immature data. We've said publicly that you gotta be north of kinda 20 patients, our observation anyway. You gotta be north of kinda 20 patients before you can start to really make a call.
You know, right now I can tell you if you look at the Swimmer plot in our corporate deck, we have three patients that are nCR at nine months. We have two that are nCR at six, and I believe the number is eight that are nCR at three. Some version of at least the first five need to read out before we'll sort of talk about that 12-month number again, 'cause, again, we wanna do so in a manner where we can, you know, feel good that the number is interpretable. Look, if the number is below 30 and sort of like, eh, does.
Like, we'll say the number's below 30 as soon as we can say that with authority. If the number gets to a place where we can say with authority that investors are wanting us to get, we'll say that as well. Right now, think about it as at least six months from now because we still have those two six-month CRs to read out to 12.
Right. You are always targeting the academic conferences.
We like to do that, yeah.
Understood.
The good news is this, is that, you know, this 31 patient naive cohort will always be maturing, right? Will always be in a position where at any given sort of canonical moment to release data to the urology sort of world, we can always do that with that data set. It's not like we're gonna go dark on NMIBC. You know, we just now have this opportunity where we feel we've answered the question on approvability.
Yep.
Now let's look at this incredible opportunity we have with the lymphatic malformations program. Is that a good segue for you or are you still?
One last question?
Oh, okay. All right.
... on NM-IBC.
All right.
So the-
Oh, I'm sorry.
Sorry. The question sometimes we get on positioning.
Mm
... is there's gonna be multiple very expensive agents.
Mm-hmm
... coming to the market in a, what is usually a community urology setting.
Yeah.
just to make sure we fully interrogate this.
Yeah
... this positioning piece.
Sure.
How do you really think about where then TARA-002 fits in?
I think for us, 002 sits sort of at the intersection of frankly everything that urology patients and providers care about. I think we can all argue, for those of you that haven't seen yet, we have arguably the cleanest safety profile of any product in the NMIBC setting, either approved or in investigation. We also have an incredibly well-tolerated product.
Now, that matters in a world where we're putting pretzels in and we're doing other sort of stuff. This is a five-minute administration of a drug that is very well-tolerated, very, very safe, and is now demonstrated that we are at the top end of the efficacy range when the N is interpretable. I think that that is sort of the best of all worlds.
Truly, you know, we haven't even talked about sort of the, what are generally more commercial characteristics, but not unimportant: ease of use, tolerability, no freezer, no special handling. We can manufacture 20 million vials every year and can 6x that if we need to. It will never be in shortage. You know, five-minute catheterization, doctor doesn't have to be in the room.
You know, there's another company out there that kind of leans heavily into that as their main investment point. That's just one-third of our investment points. This market becomes a market not of heterogeneously conducted scientific experiments, but one of commercial products, we feel really confident. The other thing to think about finally is we have sub 1% COGS.
That gives us so much power when the conversation is commercial as it relates to trade and distribution terms, you know, providing volume discounts to urology group practices that are, at this point, 35% owned by private equity. Like, that's where the adoption factors really kinda come into play. To me, it's top of the range efficacy, best in class safety tolerability. No one's got an easier to administer product than we do.
Okay. If we could segue into lymphatic malformations.
Mm-hmm.
Clearly, as you mentioned, standard of care, ex-U.S., with some updates already disclosed.
Mm-hmm.
sounds like we're gonna get some update on the regulatory path in the first half this year.
Mm-hmm.
Maybe level set expectations.
Yeah. Here's what I, here's what I can confirm. We have a Type C meeting scheduled with the FDA, that final minutes from that meeting will come to us in the second quarter. You know, that gives us an opportunity to, I think, answer one of the questions that's out there, which is, you know, what is your regulatory path? Obviously there is this sort of adjacent company and lymphatic malformations we do not compete or overlap in any way, but they're sort of at the vanguard of, you know, orchestrating or articulating what an LM's opportunity could be.
You know, look, I think, they have a degree of regulatory clarity that we have not been able to articulate, we will be able to do that in the second quarter of this year. Obviously, we're due for another data update. We continue to enroll and dose kids. The last update was in November.
I would just point out that there are two medical conferences in the second quarter this year that are related: Society of Interventional Radiologists in Toronto in April and ISVA, which is the Vascular Anomalies Society, their conference is in mid-May. Those timelines line up for pretty nicely for a regulatory update.
What is the path to registration, and is the drug continuing to be durable, and how is it behaving as the N goes up? Are we still seeing these monstrous effect sizes of, you know, kind of a 100%-
Yes. 100%. Yep
... you know, clinical success in evaluable patients.
Okay. One question we also get is clearly the value and potential pricing-
Mm-hmm
... in NMIBC versus lymphatic malformations.
Yeah.
How do you reconcile the two?
Yeah. We like to think of it as sort of the Avastin-Lucentis model . You know, if you've got two dosage presentations, two different SKUs, brands that are... for whom revenue is auditable, then indication split works. If you don't, indication split doesn't work. Just to draw the comparison, our utilization of OO2 in the lymphatic malformation setting is 1 KE. It's 40 times that for in a vial of for the NMIBC, it's 40 KE.
Because, you know, in the 1 KE, you're talking about tens of billions of cells, it's obviously hundreds and hundreds of billions of cells. Actually to stabilize the lyophilized pellet, there's different excipients in that. Different dosage presentations, different excipients, different brand names, likely different NDCs, likely different J-codes, different brands, different distribution channels.
That's how you kind of get differential pricing. Frankly, the pricing in NMIBC is, you know, thank you, J&J, it's so robust that we've got a lot of flexibility in how we differentially price these. You can expect in LMs, if you are providing a functional cure to these kids in two doses on average, the HEOR of that, the sort of the health economics is through the roof. We'll price any product in our portfolio according to the value that it provides for patients.
Okay. Understood. Remind us the lymphatic malformation opportunity in the macrocystic and maybe a mixed population.
Yeah. You know, we address Macrocystic and mixed cystic lesions. These are the large balloon-like sort of malformations. There's about, let's call it between 1,400 and 1,800 live births per year in the United States. Remember I just told you it's a functional cure, so you're kind of thinking more on the incident model than you are on the prevalence model.
That it's not the only one. Let's say that, you know, what we know is about 67%, about two-thirds, of LMs diagnoses are Macrocystic or mixed. For easy math, let's say that the birth rate is 1,200 patients, that means 800 of those patients are gonna be Macrocystic patients. There is no approved product.
Our mechanism of action is highly differentiated and specialized relative to sort of generics that may be used off-label willy-nilly to try and address these malformations because I gotta trust me, if you had a kid with a 1.7 liter malformation, you would do anything to have that eradicated, especially before that kid enters school age.
If you think about that number, like 800, you know, in good years, maybe it's 1,000, kind of addressable macrocystic patients, assign whatever sort of penetration you will to that. What we know is that these kids all tend to migrate towards vascular anomaly centers. There's probably about, I think Bill Conkling, our Chief Commercial Officer, keep me honest here.
You can address about 80% of the patients seeking treatment by covering kind of, you know, 50-100 of the vascular anomaly centers in the United States. There's this prevalent population, and that's harder to pin down. Again, we benefit from this other company that's adjacent to us doing a lot of claims analysis. You know, there is no delineation in diagnostic codes between macrocystic and micro. You gotta kind of assume it's all there.
There, some of the work that they've done suggests that the prevalent population is about 80,000 patients. The literature says 20,000, but split the difference. Those patients are. Because they're prevalent, they're living with their disease. They're either living with their disease because it's not profound enough that they seek treatment or, as is more often the case, they're treatment apathetic.
Meaning when they were in school age, they were treated with surgery, with sclerosing, which both have very high recurrence rates, and by the time they're in their late teens and early twenties, this is where we see a lot of that prevalent population, they're treatment apathetic. You gotta go into the community because they're no longer coming to vascular anomaly centers. You gotta go into the community. We're not gonna do that.
That's the job for patient advocacy. What's beautiful about this setting, and I've spent a lot of time in rare disease, is the patient advocacy sort of support for these patients is in its infancy, and we can be a big part of supporting the growth of that patient advocacy group and reach those patients where they live and say, "Hey, don't give up. There's a, you know, a targeted immunotherapy that can do what sclerosins never could do.
Okay. Well, clearly a rich, pipeline catalyst path. As we end, just maybe a reminder of the choline program and just remind us about the catalyst calendar going forward.
IV Choline Chloride's phospholipid substrate replacement therapy for patients that are on parenteral support. There's about 40,000 of those patients in the United States, about 35,000 adults. Through our own observational research that we've done, what we've learned is that 80% of patients on parenteral support are choline deficient, and of those, 63%-68% have some form of liver injury, right?
You can tie the deficiency to sort of downstream sequelae. You know, that is a really big rare disease population. I mean, it's sort of on the order of CF or DMD. There we have reached agreement with the FDA for the pivotal study that we're enrolling right now, a primary approvable endpoint of elevations in serum of choline after administration via IV of choline.
That is a very winnable endpoint. We'll also be looking at, you know, at the six-month time point at, you know, clinical endpoints, biomarkers of liver injury. There, again, it's another shot on goal with a de-risk regulatory path and a pretty significant addressable population.
All of that is to say, you know, an investment in Protara right now, you're getting in at the ground floor of what is potentially three, perhaps four registrational studies with not necessarily super difficult to achieve endpoints. You tell me. Take your pick. If you're in it for this, you're in it for that, there's a lot of ways to win.
Yep. With that, we'll end, but we really do appreciate-
Thanks, Stacy.
... your time. A clear valuation disconnect with the level of de-risk programs.
We will work tirelessly to get that value. Thank you very much.
Thank you.
Thank you to the.
Thank you all for listening.