Conference Transcript - TYRA 2026-06-03

Maury Raycroft, Analyst — Jefferies

Hi, everyone. My name is Maury Raycroft and one of the biotech analysts at Jefferies. I'd like to welcome Todd Harris, the CEO of Tyra. It's an exciting time for the company. Todd's going to give an intro with a couple slides and then we'll switch over to Fireside Chat. So without further ado, I'll turn it over to Todd.

Todd Harris, CEO

Thanks, Maury, and thanks for having me. All right, I may be making some forward-looking statements, so please be advised. I want to just start with a brief overview on Tyra. We're at a really critical and important time in the company, a really exciting time in the company. Our Dabo 3x3 strategy, which is reflecting that we are now in late-stage development for three potential blockbuster indications with our lead drug, Dabagratinib. And these are all indications that are driven by FGFR3. It includes intermediate risk NMIBC, where we're going to have data in August, achondroplasia, where we'll have data in Q4 of this year, and low-grade UTUC, where we will have data next year. Let me start briefly on just the size of the unmet need. In bladder cancer, nearly 50% of patients are driven by FGFR3, and in the intermediate risk NMIBC setting, upwards of 70, even 80%, are FGFR3 driven. That's a primary driver. The same for the upper tract indication, where low-grade lesions as they migrate up into the kidney and into the ureters can cause a significant unmet need, often leading to kidney removal. These are really large opportunities commercially. We think about the intermediate risk NMIBC opportunity as being comparable to other targeted therapies like, for example, osomertinib that treats a similarly 30,000-sized population with patients staying on drug for two years. And that's a very successful drug that is nearing its patent and is generating $7 billion in revenue. In UTUC, we also see a blockbuster potential, largely driven by this ability to spare kidneys and patients' willingness to potentially stay on a kidney-sparing drug to avoid that outcome. Now, achondroplasia is also driven by FGFR3. And so with dabrogratinib, the first oral selective FGFR3 inhibitor to enter the clinic, we have an opportunity to change the game for patients across all three indications. Let me start briefly talking about intermediate risks and MIBC. and I'd like to invite you to imagine for a minute the patient journey. Imagine 30, 40 years from now in your older years that you wake up with blood in your urine. That's typically the first sign. You would call your physician who would advise you to go see a urologist and he'd show up in the urologist's office. And there, typically a young nurse would ask you to lay out on a table, Remove your gown, and a cystoscope will be placed up through the urethra. It's an uncomfortable procedure, but it's there with that camera in your bladder that a physician would then make the original diagnosis. With those lesions seen in the bladder, the real way to understand what the stage grade of that is is to come back and remove those tumors via TURBT. That's a procedure that would get scheduled out a week or two, and you'd return to come back under general anesthesia to have this surgical procedure taken. In the process of that, the tumors would be removed. The tumors would then be sent out for pathology. You'd be invited to go home. And you get a call from your physician maybe a week or two later advising what the grade of those tumors were. In the best case scenario, you have low-grade disease. That means you're intermediate at risk. And you have now a disease of recurrence but not necessarily progression. With high-grade, it's a disease of progression. It could often lead to the removal of the bladder to avoid further progression of the cancer. So standard of care today, and 70% of patients and physicians elect this, is to post the surgical procedure, just wait and see. Despite that, as many as 40% of patients are recurring within two years and needing to undergo the same procedure. So there are approaches today to try and address this. And standard of care does allow that a patient could come back every week for six weeks and have the installation of chemo, that is an installation of a catheter, and chemo pushed into the bladder. And then as a patient, you'd be asked to hold that for as long as possible. That done every week for six weeks, every month thereafter, is an incredible treatment And as a result, as I mentioned, most patients won't elect to do this, even though this would improve the efficacy and reduce the need for a turbid again. So there are other treatments that are being developed currently, all of which take the same approach of intravesical urethral violation with chemo. That would be Urogen's drug, Zesturi. CG oncology is approaching this with a viral vector, so intravesical push of a virus into the bladder, or a pretzel, a device that would elude drug with J&J's TAR-210. All of these have the same issue that the patient journey is already facing, which is over-instrumentation, urethral violation through these intravesical administration. With oral dabogratinib, we have an opportunity to change the game, and it stands alone in its ability to address this unmet need. Because in the future, you have the potential to offer a patient a once-a-day oral option to avoid all of this instrumentation, all of the urethral violation. So with a potentially efficacious drug in this setting, a patient could for the first time have this option to really avoid the treatment burden. Now, what's the bar for success? Well, it was really set initially by a pan-FGFR inhibitor that was studied in this indication by J&J, and that was the drug ertifitinib. Here in Thor 2, and I'm highlighting some important data from a study, they were able to show an exceptional outcome in terms of efficacy. The best overall response was an 89% CR rate. This was, and the duration of response was remarkable because for every patient that stayed on drug, the duration and efficacy out to 12 months was 100%. Furthermore, several patients who initially started with PRs, as long as they started on drug, converted to CRs. Clear evidence that the drug is not only shrinking the tumor, but also keeping any tumors from coming back, which in an adjuvant setting is exactly what the goal is. So with 90% plus patients getting the benefit from this lower dose of ertifitinib, the efficacy opportunity here in an adjuvant setting with these type of results would be astounding. Now, the challenge with ertifitinib is the toxicity and safety profile. It was untenable for patients. Despite lowering the dose, there was very high rates of dose reduction, 61%, discontinuation, 78%. And it's driven by the FGFR1 and 2 tox that you see with the pan-FGFR inhibitors. And it's the very tox that we at Tyra were able to demonstrate significantly reduced when we got into the clinic with dabogratinib. Now, J&J ultimately put this into the device the pretzel. That had good results. That's now in a phase three study, but it needs to be locally administered through the pretzel because of these AEs. And if there was an opportunity to do an oral, obviously J&J first testing that, that would have been preferred. Now, what are the challenges with some of these localized devices? Well, when you look at the label for or the pretzel in Lexo. You can see a lot of significant local AEs. Discomfort, pain, high rates of UTIs. And when you look at the Zesturi, this would be the chemo gel that's approved. In the intermediary setting, again, you see a high rate of local AEs. These are not, these devices aren't walks in the park. Our approach here is that we are gonna look at two doses, first in a signal-seeking study, the SURF 302 study, which is going to read out initially in August. This would read out with a total of about 20 patients for efficacy, a much larger patient population for safety, 30 plus, 10 patients at each dose, and we're going to look at this initial three-month CR rate. For a very long time now, we've highlighted that we believe a 70% CR rate or better would be lights out data and would be enough to select a dose and to move into phase three. and the reason is again that this oral approach really changes the game the unmet need is the treatment burden and so when comparing to an intravesical device or TURBT it's really not the comparison for efficacy the comparison for efficacy for us is what we saw in Thor 2 and it was 100% of patients staying on drug continued to see 100% durability it was that any PRs converted to CRs, and you saw this, you know, exceptional migration towards improved therapy, even as the duration of the therapy extended. Daily oral treatment with a targeted therapy has this promise, and none of the intravesical approaches can deliver this, because those intravesical approaches can't be delivered every single day. So with the SURF 302 data, a 70% three-month CR rate, which would largely be in line with Thor 2, and which has been our bar now for a very long time would be an exceptional outcome for which we would select a dose and move forward. And key to that is we want to see tolerability and durability that is again exceptional. So the tolerability bar that we've set is similar to our metastatic setting in a 60 and 40 milligram dose. We saw very modest rates of grade one or two events. We would expect a very low rate overall of any grade 3 events. We typically, you know, talk about that as in the single digit percentage. That would be in line with TAR210, for example, which sees about 5% grade 3 events. And a low frequency of diarrhea, a low frequency of ALT, AST, everything in line with what we've already seen in a patient population in that metastatic setting. the reason that this bar is right for us is that we're looking to run an adjuvant phase three and in an adjuvant phase three you actually remove the tumor up front and then you're looking at a disease-free survival endpoint so it's all about durability tolerability patient staying on drug and if we see the type of results that we saw that thor2 saw where 90 percent of patients were having drug effect, you're talking about a very compelling hazard ratio that could ultimately drive a great outcome. One last point on intermediate risk NMIBC, we often get asked, well, what about an oral? Don't physicians love their procedures because they get paid for procedures? The reality is there's already a very robust system in place in the community setting where the majority of docs treating intermediate risk NMIBC are, where the majority of patients are seen that has allowed for these physicians to have their own in-office dispensed pharmacy to dispense drugs like Xtandi and Orgovix, and as a result of that, what you're seeing is a very compelling move towards increased revenue in the practices from oral drugs. The main point here is if you talk to a community urologist, they're really happy about delivering oral drugs to their patients. It's best for the patient and it supports their economic model with their own in-office dispensed pharmacy while cutting down on some of the laborious time that their nursing staff would be required to deliver some of the procedures that were there before the drugs came along. So let's talk about UTUC just briefly. In UTUC this is a rare disease with a significant unmet need And the key is that these low-grade lesions that we talked about in that intermediate-risk NMIBC setting show up in the ureters and in the kidneys. As a result of that, they're very hard to remove with surgical intervention. And as a result, many patients, potentially half or more, are going to ultimately see their kidneys removed. Gelmito is the one approved therapy. It paved a very attractive regulatory path that we're looking at, which would be a single-arm study for full approval of about 70 patients. We're looking to do the same thing once we get our dose right, and we're guiding towards 2027 being the initial data set where we could actually see the dose that we want to move and go forward. And when we talk to physicians about this, they indicate in almost every setting they would want to try and use an oral first before the significant intervention required to try and spare the kidney or just the complete removal of the kidney itself. So, Maury, I want to give plenty of time for you to ask questions. So the last part of the program, and I'll just hit on this very briefly, is achondroplasia. We're guiding now to data in Q4 from our safety sentinel cohort. We've cleared all four doses that we were testing, which means that after a 30-day period of at least three children being on each of the doses, no safety events emerged, allowing us to move forward with a broader treatment group at each of these doses. So we're looking at the first 12 or more kids at the four doses having a six-month AHV readout in Q4 of this year. So that's Tyra. It's been an evolving and exciting story. We have an unbelievable opportunity to change the game for these patients. We're moving into late stage development. We have three blockbuster indications, well-financed for at least the first indication and UTUC to get that all the way to an NDA. And if we see the data we hope to see as we read out some of these phase two results, we would look to raise additional capital to fund phase three so that we get all of these drugs to market as quickly as possible. With that, Maury, I'll hand it back to you and look forward to the questions.

Maury Raycroft, Analyst — Jefferies

Yeah, that was really good, Todd. Good overview. If you want to come over here. So, yeah, maybe starting off with the data update in August. So it's going to be an exciting update for you guys. You've guided to greater than 10 patients per cohort, 10 or greater patients per cohort. I guess what's the realistic upper bound for a number of patients who could have a first scan by the cutoff?

Todd Harris, CEO

Yeah, we were very explicit with guiding towards that August date so we can ensure we have 10 patients at each dose. So that's really what our target is. We would have potentially could have quite a few more for safety because we continue to enroll. So the 20 patients are all ones where we know their dates, their dates of their systole. We'll be able to essentially read that data out to report on an initial result.

Maury Raycroft, Analyst — Jefferies

Got it. And for the 70% CR benchmark, you talked about the Thor 2 data. When you think of the 70%, does that set like a conservative lower bound, or do you think approximately 70% is appropriate for intermediate risk patients?

Todd Harris, CEO

Yeah, we've said for a very long time 70% is the bar. We initially heard that from KOLs really years ago, so we've been consistent about, you know, we think that's a meaningful signal. What's interesting when you look at the Thor data, that's actually very consistent with the Thor data because if you do cut the Thor data at three months, there were about 72% of patients that had seen a CR at that point. What's interesting is that you then evolved that data forward and 89% got to CR. So you had a number of patients that were on PRs, and any patient that had a PR at three months, as long as they stayed on drug, actually moved to a CR. And then as we've talked about, as long as they stayed on drug out to 12 months, no one recurred.

Maury Raycroft, Analyst — Jefferies

Yeah. Yeah, it's a key part of the ertifitinib data, I think, is that you do see this deepening of effect over time. How do you think about durability for dabigratinib relative to fixed-dose intravesical options?

Todd Harris, CEO

And then what's the durability bar that you're aiming to clear eventually? really important point and and you know it's you know we should not be compared to the intravesical options because the intravesical options you can achieve a hundred percent cr by using a turbot procedure to cut the device out and you can achieve a high cr by installing six different installations of chemo uh through the catheter but the point is that once you're done now you're putting no intervention on the tumor so what you see is you see this regression at six months and nine months and 12 months. So your landmark CRs start to fall down. With an oral therapy, it's quite frankly the opposite. You know, your PRs progress to CRs, your duration continues. And so where differentiation can really result is out at 12 months and 24 months, where an adjuvant study where we're measuring recurrence-free survival, where you could really win. So for us, a 70% three-month CR, which we've highlighted for a very long time, it actually predicts, if you look at the Thor2 data, a long-term outcome that would be superior for the devices. And it's because of this mechanism of action. And the key is, as long as the dose is well-tolerated so that the majority, if not all, the patients just continue to stay on drug, then you are allowed to really have that enduring effect because of the daily pressure on the tumor.

Maury Raycroft, Analyst — Jefferies

Yeah, that makes sense. And you showed the three-month data in August. You'll have some patients that are beyond three months as well, potentially. And then you'll have more time points that you'll show data updates on later on as well. Talk about just the cadence of data.

Todd Harris, CEO

Yeah, we're really entering into a data-rich environment August is our first shot to look at whether we have sufficient data to pick a dose and move into phase three. But there'll be maturing data thereafter. So more patients at these dose levels and then looking out at, you know, the next three-month scan against the next nine- or 12-month scan. And we'll guide to when the next data set would be. We're not giving any of that guidance yet. So that is, I think, the really meaningful part is we can be tracking durability.

Maury Raycroft, Analyst — Jefferies

And we can be doing that whilst, you know, kicking off very quickly at phase three. as long as we get that sort of minimum criteria at three months we'll have full confidence that the the dose we're going to select that would be the right dose for phase three got it so that'll be enough to inform phase three dose and and uh got it um and uh for safety so in uc you saw the liver toxin you talked about this uh with some of the safety signals that you see with uc at much higher doses should we expect these aes to be lower at nmibc how frequent and um would you expect any grade 3 liver tox, or do you think that's unlikely?

Todd Harris, CEO

Yeah, we're not expecting to see grade 3 liver tox. At 90 mgs and higher, we did see grade 3 AST-ALT. They could be managed by bringing patients off drug. When we got down to 60 mgs, we had one low-grade ALT rise. So as we look at these doses, the expectation would be consistent with that. If you also look at the labels of Lexo and Zesturi. AST-ALT increases about 15% to 17% in those patients, despite this being a local therapy. You're talking about these systemic effects. If you look at Thor 2, at the 9 milligram dose in the metastatic setting, 45% AST-ALT increases. That moved down to 17% when they brought the dose down to 6%. So we're expecting from our MUC day a precipitous decrease in the the liver signal, and for it to be, you know, very modest at most. And, you know, that's obviously something that we'll benchmark to. But if we're hitting similar benchmarks to the on-label and approved drugs that are localized, you know, I think that's a great benchmark to cite. That's probably the most important thing we're looking at, quite frankly, because that was the thing that we saw the signal decrease the most when we went from 90 down to 60. Other things like diarrhea was at such a modest rate that when we look at, for example, placebo-controlled studies from Xtandi, you see 20% low-grade diarrhea. That's exactly consistent with what we saw in the MEC study. And so that's probably the lower bar, you know, in a patient population like this. And there's really no other signal that was driving, you know, a large percent of AEs. So, you know, in the absence of those things, or with focus on those things coming in line with our expectation, and then no other signal showing up as a major percent event, I think we're going to be in a really excellent spot. We already showed with the 90-mig dose that the things that patients, you know, that's most uncomfortable to them have gone away. The nail talks, the eye talks, the PPE, the stomatitis, all of those things were markedly reduced down to levels that were very acceptable, even at the 90-mig dose.

Maury Raycroft, Analyst — Jefferies

Got it. I'll make sense. Vincent, for CG Oncology's Pivot 06, for that readout coming up, what elements of the readout are you most focused on, and what's the cleanest read-through to your program?

Todd Harris, CEO

Yeah, so, you know, just like we talked about with the chemo installations post-Turbit, which are standard of care, but not used today, right? They're 70% of patients and physicians are not opting to do that. We would expect a CG Oncology-type approach, where you're putting a virus into the bladder every week for six weeks with potential maintenance after that to look and feel very similar to the patient and what they're experiencing today. And remember, even though chemo installations are efficacious, potentially more efficacious than just doing turbot and wait and watch, patients are electing not to do that because the treatment burden is really the unmet need. And so if they wait and watch, it cuts down on all of these installations. If they do need another turbot, so be it they do another turbot. So really, the thing that's most important to us here, and I'm not sure what the readout will be. They didn't run a phase two, so it's a little bit hard to predict. But what will be key is looking at, in a randomized study, and they were comparing to observation, what are the rates of events that you see in that observation arm? That will inform our phase three design. We would look to a very similar adjuvant-type phase three design. Rather than observation, though, we would do placebo. That would give us a chance to actually understand the AEs, whether they're just underlying or drug-driven, because we would have a true placebo study. It would also, you know, really highlight the potential benefit of what's used today in standard of care, which most people are just doing wait and see. So if we meaningfully change the recurrence-free survival curve, have an excellent hazard ratio, which we think good data in SURF 302 would predict, then that's, you know, just an exceptional outcome. The last piece is CG oncology's looking at high-grade tumors. We would just focus on low-grade FGFR3 positive tumors. So there's going to be some differences in the population, but again, that observation arm should at least help us inform somewhat how we would want to power the study and what type of events we might see.

Maury Raycroft, Analyst — Jefferies

Got it. Makes sense. And I think your walkthrough of the treatment burden makes a lot of sense. I think it's one of the things that clearly should resonate with patients. But how do you think about just getting doctors on board with an oral-based approach when they're so used to treating patients with intravascular therapies?

Todd Harris, CEO

Yeah, I think in the community setting, where 80% of intermediate risk NMIBC patients, it's a misnomer to suggest that these physicians aren't used to using orals. And I want to be really clear on this, because if you talk to a KOL at a big academic medical center like MGH or Memorial Sloan Kettering, they don't prescribe orals. Prostate cancer patients get sent over to MedOnc. But when you get into the community setting, where a lot of prostate cancer patients are still treated, those physicians have been trained and experienced on giving orals. And really the best case study to highlight why their experience is deep, why an oral can be very attractive to them, is the recent launch of Orgovix. Where Orgovix replacing Lupron for medical castration has gone in five years to completely changing that procedure to an oral. They now have majority share. It's a blockbuster indication. That's exactly the model we're talking about. We want to bring an oral where there's procedures today and where the attractiveness of the patient is high. And the reason that the community urologists are able to make this transition to a procedure of an oral is that they all have, for the most part, been able to put in their own in-office dispensed pharmacies so that it can be a practice revenue driver just like the procedures used to be. And so they're not economically disadvantaged when they make this transition. And this was established for the last 15 years through the launch of drugs like Xtandi. These are $4 or $5 billion drugs that have very successfully brought procedures to orals in the urologist's office. So when you think about us, really the comparison shouldn't be to intravesical therapy and procedures. It really should be to some of these case studies in prostate cancer drugs that have been very successful, or Govix and Xtandi.

Maury Raycroft, Analyst — Jefferies

Got it. That's helpful. Yeah. And maybe talk about pricing. Are there good benchmarks in the space? And how do you think about pricing for intermediate risk disease where progression risk is lower, but recurrence risk is meaningful?

Todd Harris, CEO

You know, we hear repeatedly that the intermediate risk setting, it's one of the most expensive disease indications. And it's driven by repeat office visits, the nursing staff, the installations, the burden on the patient. And when you really start to calculate that up, it's an immense amount of money and burden that's actually spent on all of these procedural devices um so from a pricing perspective we're looking at innovative drugs like ertifitinib innovative drugs that may come along like tar 210 and some of the guidance we've seen there as being sort of the right right comps um potentially some premium for a fgfr3 selective that's solving all of these unmet needs but um those are great benchmarks and you know when you sort of look at that you compare it to the size of the population, 35,000, you look at the treatment duration where patients would likely want to be on the drug for 24 months, all of a sudden you're looking at the size of opportunity that you're capturing with the drug, like Tigriso or Osimertinib, for example.

Maury Raycroft, Analyst — Jefferies

Got it. Makes sense. And for achondroplasia, if I heard you right, you said you cleared the fourth dose and you're not seeing any safety signal there?

Todd Harris, CEO

Yeah, that's right. The checkmark says no safety signal seen in that 30 days, good to go. Got it.

Maury Raycroft, Analyst — Jefferies

Okay. So no DLT at the highest dose, nothing there. Nope. Got it. Okay. And for this achondroplasia update later this year, given there's no controlled baseline data and escalation cohort, how should we think about the baseline annual high velocity for the enrolled patients?

Todd Harris, CEO

You know, it's so well established now that especially in an age 5 to 10 population, the baseline is going to be around 4 centimeters. The placebo is going to be around 4 centimeters. So that's the comparison. We want to look at getting to above 7 centimeters at 6 months in terms of AHV at the highest dose or the highest doses. The dose response curve kind of pushing towards that area will start to demonstrate our thesis that further target engagement can really drive more meaningful growth than was seen with the other agents to date.

Maury Raycroft, Analyst — Jefferies

Got it. And is infragratinib, the phase 2 data at 6 months with about 7 centimeters per year, is that still the right benchmark?

Todd Harris, CEO

Yeah, I believe it was 6.8 or 6.9 centimeters, six months, HV in their phase two was that they reported out. We want to add a centimeter to that. So that's what we're going to be looking for.

Maury Raycroft, Analyst — Jefferies

And when do you expect to start enrolling cohort one and cohort two in expansion? And given the six-month baseline requirement, when should we expect initial data from those cohorts?

Todd Harris, CEO

Yeah, we've been enrolling in cohort one and two for some time now. Enrollment is quite robust. And so as soon as they come up on their six-month window, they're going to convert into one of the active doses. So we're going to see a rollout coming out of the 4Q event of potential additional data readouts getting into 2027. And we're going to look to leverage what we see in the central cohort to move towards a phase three as quickly as possible.

Maury Raycroft, Analyst — Jefferies

And following Biomarin's success in hypochondriplasia, what's your timeline to start a hypochondriplasia study? And how do you think about the market opportunity there?

Todd Harris, CEO

You know, I think it's a great opportunity. Biomirin just put up some really exciting data. I think for an FGFR3 inhibitor to kind of clear the benchmark or hit that benchmark with an oral would be a great outcome. We do think about this as you may need a higher dose than achondroplasia because of the way that that particular mutation changes the drug's action in the active site and its ability to outcompete ATP, which is the fundamental way in which these oral drugs work.

Maury Raycroft, Analyst — Jefferies

Got it. And for UTUC, what response rate and durability threshold would you view as clinically meaningful versus standard of care?

Todd Harris, CEO

Standard of care is dismal, let's be honest. You're going to get your kidney removed in the most likely scenario, you're going to have these horrible operational procedures, or you're going to have this chemo gel with a hole drilled into your back, pushed into the kidney. That's the best we can do. When we talk to physicians about even a very modest CR rate, they're going to put every patient on a drug like that if that's what we're to see. But importantly, if we look at the data that Serenomateen generated with infragratinib, only six weeks of treatment looking at a 12-week result, 67% of patients had an ORR. That's 67% of patients starting to benefit. So if we have a well-tolerated drug, With an ORR, whether it's a CR or PR of that range, the majority of patients are not only going to get the drug, but then they're going to stay on the drug. And if they continue to see benefit, that continues out to 12 months and beyond. Now you're talking about really changing the game for the patient and changing the prevalence population of individuals that have spared their kidney and would like to just stay on drug to keep their kidney.

Maury Raycroft, Analyst — Jefferies

Got it. And for enrollment for this year, maybe talk about where you want to be by the end of this year and how many sites opened.

Todd Harris, CEO

And yeah, we're actively enrolling sites. This quarter, we have an initial bolus, but we have plenty more sites to activate. Sorry, I used the word enrollment. So we'd like to activate as quickly as possible over the next few months. We're seeing really great excitement. Folks like MD Anderson and Cleveland Clinic are now open and screening patients. We dosed our first patient. So we'd like to see that enrollment start to inflect, especially as we get more sites active in the months ahead. and then we'll guide to when we'll have data once we see that curve. Got it.

Maury Raycroft, Analyst — Jefferies

Okay, thanks so much for joining us today, Ty.

Todd Harris, CEO

Thanks, Maury.