This is Maury Raycroft, one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome Todd Harris, the CEO of Tyra. Thanks so much for joining us today, Todd. Thank you, Maury. Happy to be here. And we're going to do fireside chat format. So maybe to start off, for those who are new to the story, if you want to give a one-minute intro on Tyra. You bet, so Tyra, we're a company that makes small molecule precision medicines. Our lead drug is an FGFR3 selective inhibitor. It's actually the first oral FGFR3 selective inhibitor to be designed to get into the clinic, and we're also the first to read out clinical data, which we just did last month, and the data were excellent, exceeding our expectations, both in terms of efficacy and an FGFR3 positive-driven metastatic urothelial population, but also in terms of safety, which was a key reason why we designed the drug to overcome the FGFR1, 2, and 4 associated toxicities, which we were able to demonstrate very favorably with this first data readout. We have other drugs. We've made an FGFR2 inhibitor, TYRA-200, an FGFR4 selective inhibitor that's been cleared to move into the clinic. With our lead drug, we're also moving into achondroplasia with a study that was cleared by the FDA to proceed in the past month as well. We'll be treating children in short order with that drug as well, children that have achondroplasia or dwarfism, which is a condition driven by an overactive mutation in FGFR3. Got it. Yeah, I think that's a great intro. And yeah, a lot of progress over the last couple of weeks. Maybe digging into the update at Triple meeting where you had the metastatic urothelial cancer data. Talk about that. You showed a pretty impressive response rate with 54.5%, which is better than one of the key benchmarks in the space, erdafitinib, which shows about a 35% response rate. Can you discuss what else you need to show in terms of efficacy and safety to differentiate versus erdafitinib and have a clear path there? Yeah, I think what we showed was clear differentiation. We set a goal for ourselves to hit the benchmark that erdafitinib hit at 35% ORR, and we exceeded that, hitting a 54.5%. That's the best data that's been shown out there, and we think that's driven by the fact that we're able to achieve an FGFR3 selective profile. Erdafitinib is associated with a lot of toxicity that comes from FGFR1 and 2 activity. We were able to reduce that significantly across the board at doses that were highly efficacious with 100% anti-tumor activity at 90 milligrams and a significant reduction in any 1 and 2 associated toxicity. So great outcome. Obviously, it's just the beginning. It's our first data set, so we need to move through the additional studies for a late-line metastatic approval. But it was a really important data set showcasing how compelling this molecule can be in two other indications that are actually leapfrogging this indication in terms of timing for a phase two, the first of which is achondroplasia, where we're already now cleared to proceed into phase two. And the second is an NMIBC study that we're planning to submit an IND for before the end of the year. Got it. Yeah, so maybe talk a little bit more about the safety benefit and profile that you're seeing with TYRA-300. There was discussion around liver enzymes. It was one thing that came up following the Triple meeting data update. Maybe talk about that and how that factors in. Yeah, I mean, I think first off, let's highlight erdafitinib's associated with FGFR2 toxicities. 70% of patients have nail toxicities. That one in four patients are dose-reducing as a result of that really painful nail tox. 63% have stomatitis. One in five patients are reducing because of stomatitis on erdafitinib. PPE and eye tox as well. We saw across the board significant reductions down to maybe one at most two patients out of 15 that saw largely, if anything, a grade one or two event on our drug. On FGFR2 toxicities, that's a phenomenal outcome. On FGFR1 associated toxicities, hyperphosphatemia occurs in 76% of patients on erdafitinib. That was reduced down to just two out of 15 patients, all low grade. So a really remarkable outcome. On diarrhea, erdafitinib sees about 60% of patients with diarrhea. We moved that down to 20%. The one signal that was on par between the two drugs and, in fact, all the pan-FGFR inhibitors were ALT and AST increases, so these are liver enzymes. It's not liver toxicity. These are asymptomatic increases. Many patients come into study with those increases due to liver mets or other issues as a late-line elderly population, and these can be managed very well. It only led to about 5% or 6% dose interruptions with erdafitinib in the metastatic setting. We're seeing a similar rate, largely low grade. The majority of patients actually don't have the increases, and so it's really the one activity that we see on drug. It's very common with the pan-FGFR inhibitors and TKIs, and remarkably, we see when we go down to doses that are relevant for NMIBC and achondroplasia, we see it completely go away. We saw no treatment-related AE events at 40 mg, the highest dose we'll treat in kids with achondroplasia, none, and we saw one out of 10 patients starting at 60 mg. And that was a grade one ALT increase. And that's a very acceptable profile for NMIBC. So generally, we're very excited and pleased with the safety tolerability profile we're seeing. Got it. That's all helpful. And one of the questions that's come up is whether the liver enzymes, if that effect could accumulate over time with the lower doses for achondroplasia or NMIBC. So I don't know if you have perspective into that? Yeah, we don't see any evidence to suggest that. I mean, we had patients start on 40 mg, which is the relevant dose for achondroplasia, dose up to 60 mg, and stay on drug for over a year, and really no impact. So we're very encouraged by what we think we'll be able to achieve at a 40-mg dose. Certainly, when you push these higher doses, you tend to see some AST/ALT. They're asymptomatic and on par with the other drugs in this space. So that's and that dose dependency is really clear as well in the data. Got it, and also just one question on the hyperphosphatemia too. Can you clarify the method used for that to measure that and compare it to other methods that are used for hyperphosphatemia with the erdafitinib label? Yeah, in the data we disclosed, we actually disclosed this in two different ways. So CTCAE guidelines specify what constitutes a grade one, grade two, grade three event. So we reported our frequency of grade one, grade two event. That's essentially driven by the rating of the investigator. We also just showed the frank phosphate level numbers, highlighting that for the most part, we are all within the upper limit normal, and we drew essentially bars to show what would be a grade one event. And the vast majority of all patients are beneath that. We had one patient with a phosphate binder out of 41. That was actually preemptively given before they reached the 7 milligrams. That is typically the CTCAE guidelines that are followed for giving it. So the phosphate levels were significantly reduced relative to what you would expect to see with a pan-FGFR inhibitor. And we highlight that data in our release. Got it. That's helpful. And with the safety benefit that you're seeing, you're seeing clear benefit versus erdafitinib on several measures, which you said lead to dose interruption for patients on erdafitinib. And maybe talk about how that could potentially translate to durability and maybe set the bar for success for PFS and OS, what you would want to show in the metastatic setting on those measures. Yeah, this was an early data set where we didn't anticipate having a read-through on PFS. So certainly, as we accumulate more patients, three of the six confirmed PRs, the patients were still on drugs, so we weren't able to calculate a duration of response. But that will certainly mature as we add patients in the metastatic setting. I think what's most important is when you talk to physicians about their interest in prescribing erdafitinib, there's a really strong reluctance because of those drivers of dose reductions, the nail tox, the mouth tox, and PPE and eye tox. So being able to demonstrate the level of reductions we've seen is really compelling to physicians. And we think it'll change the nature of prescribing in that late-line population where all the other alternatives are essentially alternatives with high toxicity. Having something that's targeted and well tolerated in that setting is really attractive. But again, our focus in some of the biggest opportunities actually shift to the earlier stage disease, non-muscle invasive bladder cancer, and then, of course, skeletal dysplasias as well. So we've got, while that metastatic setting is important, we're actually going to be moving very significantly and quickly forward on some of what we would consider the bigger opportunities. Got it. And yeah, segueing to those bigger opportunities, one other question just based on PK. It seems like the lower bound of the expansion cohort at the 40 mg dose is closer to FGFR3 IC50. What's the ideal inhibition level for these three different settings that you're pursuing? Yeah, it's a great question. So we have pretty clear expectations around dose that are driven by all of our preclinical data and now coupled with clinical data. And what we know, and we'll start with achondroplasia, what we know is that an IC90 inhibition is not desired largely because of the amount of bone growth you could see actually can start to be so fast that you might lead to fractures and other issues. So you actually want to avoid getting to an IC90. An IC50 from our preclinical molecules is right on target for what could be a very meaningful and safe level of FGFR3 inhibition. And it's a level of FGFR3 inhibition that can't be achieved with a pan-FGFR inhibitor. So that's an exceptional opportunity. That's exactly where we're going with our four doses from 0.125-0.5 mg per kg. It's essentially equivalent to an adult dose of 10-40 mg. At 40 mg, the highest dose we plan to test, we saw no hyperphosphatemia, no impact on phosphate levels, no AST or ALT increases. We expect a really safe window while maintaining a level of FGFR3 inhibition that hasn't been achieved. That IC50 average, if you will, we think can drive a significant benefit in terms of long-term efficacy in the skeletal dysplasia populations, especially achondroplasia. Got it. That's helpful. And for the biomarker data you showed at the Triple meeting, maybe talk about that and how important that is and could that be useful for achondroplasia and NMIBC as well? Yeah, I think the biomarker data we showed is probably more helpful for the metastatic setting because it was really driven by that high IC90 suppression. What we were able to demonstrate is that what you would typically see go up from FGFR1 suppression, which is the FGF21, we didn't see that change. You typically see that go up with pan-FGFR inhibitors. The two signals we did see that correlated were actually CXM, FGF19. And that's particularly interesting because we know that there is FGFR3 in hepatocytes as a receptor. It's next to FGFR4. And those are signals you typically see with FGFR4. We have a program in hepatocellular carcinoma where FGF19-driven HCC we know is driven through both FGFR3 and 4. And so it helps validate that program as we move into the clinic. We did see some collagen signal, which we also think is probably FGFR3-related. But I think the more interesting biomarkers will be in some of the more traditional biomarkers in achondroplasia like CXM. And there, your growth plates need to be open to be able to see that signal. And we anticipate we'll be able to see that signal at the lower doses we're testing for achondroplasia. Got it. Okay, interesting. And maybe segueing to the two phase 2 studies that you're going to be starting for NMIBC and achondroplasia, what do you need to do to get those studies up and running? And what's going to be your next update or catalyst cadence for these two settings? Great question. Yeah, so we are clear to proceed by FDA for our achondroplasia study in the U.S. The next steps are obviously to leverage that protocol and move quickly into the other countries where we want to have regulatory approval to move forward in treating kids and then opening up our first sites, which will likely first be in the U.S. and then in those other countries as well, and then begin patient dosing. And the first patients we'll be dosing will be in a safety sentinel cohort. And that'll be data that's open label that we'll read out pretty readily as we get into next year. And then meaningful six- and 12-month AHV data coming out of that sentinel cohort will be the first data that would be shared, followed by these cohorts that we're filling up in one and two, which are either treatment naive or treatment experienced with a growth-accelerating therapy with a natural history study and a more robust end behind it. So that will be the cadence of activities for an ACH readout. We plan to file an NMIBC IND before the end of this year, so in very short order. And there we'll begin enrolling patients with a three-month endpoint being the key endpoint. And that would be looking for a marker lesion complete response in an intermediate risk NMIBC setting. With erdafitinib, J&J was able to show that you can get an over 80% CR rate with a low-dose erdafitinib oral. The tolerability issues prevented them from really moving that forward. We have this extremely unique opportunity to get meaningful oral high CR rate data with a much better tolerability profile. We highlight that tolerability profile with our 60-mg dose. There we're covering the target well over an IC50. 60 mg is getting to an IC90. We saw a patient who started at 40 mg and escalated to 60 mg with an FGFR3 fusion head and neck cancer get a confirmed PR. We had patients have sustained antitumor activity with the 60-mg dose. It wasn't as great as the 90-mg, but that helps us get confident that that 60-mg dose will likely be highly responsive in an NMIBC setting. That accentuated with the fact that TKIs tend to accumulate in the bladder, and our non-clinical data show that with TYRA-300, and that erdafitinib was able to see that really high CR rate at a lower dose. So we expect to be able to cover that really well. 60 mg is going to be one of the doses. We may test a dose below. We may test a dose a little bit above. But that will, I think, set us up very well to move forward as potentially the only oral exploring this space. And in the intermediate risk setting, the majority of patients are FGFR3 positive. It's where the largest patient population is. So we're talking about a really exciting opportunity for the drug in that population. Got it. And so the goal would be to get the erdafitinib efficacy around that 80%, but with much better safety profile. Yeah, and when we talk to urologists, they say the benchmark for them isn't even that high. Even seven out of 10 patients would be an exceptional outcome in terms of CR as long as it's really well tolerated. That's what they're looking for. Got it. And anything else you can say about the competitive landscape there in NMIBC and what you're focused on? Yeah, I mean, the competitive landscape in the intermediate risk setting. It's really three procedure-based approaches. And that's from UroGen, CG Oncology, and from J&J with the TAR-210 platform. That's a drug-eluting erdafitinib device that gets placed every three months into the bladder. So we'd be totally unique in going after this with potentially well-tolerated oral. Got it. Makes sense. And for achondroplasia, IND recently cleared for that. Maybe talk about next steps there for getting that study up and running and just how the profile for TYRA-300 could compare to some of the competitor drugs for this setting. Yeah, I mean, really, really exciting opportunity. Obviously, need to give credit to the companies that have been doing development in this space. You've got BioMarin, you have Ascendis, you have BridgeBio. All of these companies, whether with the pan-FGFR inhibitor infragratinib or with the CNP peptides, Ascendis and BioMarin, have been able to show that at 12 months, they're able to get these kids to an annualized height velocity from 5.9 centimeters to 6 centimeters. It's actually a nice New England Journal of Medicine article from BridgeBio yesterday on infragratinib where they highlight this 6-centimeter annualized height velocity improvement. But that clearly isn't filling the gap. Kids without FGFR3 mutations are actually growing more than that year- over- year. And so the opportunity to actually differentiate on efficacy and get to an annualized height velocity, which is a surrogate that's much better than that, upwards of eight centimeters potentially, is the target because we believe with that surrogate, that will lead to meaningful benefit on the key endpoints that FDA and the community care about. FDA talks about final adult height, which I think getting to that higher AHV gives you the opportunity to actually meaningfully change what the other agents are going to be able to do. But most importantly are things like reach, gait, spinal stenosis, and some of the surgeries associated with it that evidence of really hitting the target the right way on AHV will likely lead to meaningful clinical benefit for this population on the things that are most important. Got it. Okay. And how easy do you think it would be to switch patients in achondroplasia from other drugs that are approved to TYRA-300? We really responded to the community when they asked us to make sure we had a cohort of treatment-experienced patients that had been on some growth-accelerating therapy. And it was really the community that said, "Patients are coming off of and not seeing the benefit they want to on CMP sometimes." And some patients have been on studies and want to be able to get on a study like ours. That's why we designed that cohort. That will give us really meaningful data to highlight what switching can do. And I think it'll be a part of the data set as we get into phase three and ultimately launch this drug in terms of the benefit of switching off of an existing therapy to something that might be able to hit the target more appropriately. Got it. And that's going to be once you start the phase 3, you would have that cohort. How big are the different cohorts for the phase 3? Our phase two has a treatment-experienced and a naive cohort. So we'll actually be able to generate data in our phase two to start to look at what does switching look like in these kids. The guidance we're getting on a phase three from FDA is that because BioMarin has an accelerated approval, they're still looking for sponsors to do placebo-controlled studies. Until there's actually a confirmatory approval, standard of care, I think that's going to be the paradigm that companies like us are going to need to operate in. Got it. Makes sense. And for the safety sentinel cohort for your phase two study, that's going to include four doses with three patients per cohort. How long do you think it would take to enroll those cohorts? And are you saying anything more about timing for that potential update? Yeah, what we're highlighting is that the way we've designed this is it's like a 30-day DLT period. So the first three children will go on a dose. After 30 days, we'll be cleared to move to the next dose. So that will naturally pace out at least one month between these doses in terms of our enrollment. But we anticipate being able to move through that fairly quickly. And there'll be a very meaningful safety data set coming out early from that experience even before we start to evaluate six-month efficacy or 12-month efficacy in that initial sentinel cohort. Got it. So you would be able to look at efficacy in that. From my understanding, it doesn't have a run-in period, so you wouldn't have the baseline AHV, but. That is right. The follow-on cohorts will. But we actually think that just the absolute AHV numbers are probably the most predictive data sets that are out there. Ascendis, BioMarin each achieved about a 5.9-centimeter AHV. They're in their phase two and phase three. BridgeBio, a 6-centimeter. Looking at it that way actually removes the variability from a 6-month measurement in a baselining period. The average child with achondroplasia is going to grow 4 centimeters per year during this period of time. That is 5 to 10. So being able to take out the variability that you might see in a baseline period, you can actually get a really meaningful read on efficacy just looking at absolute AHV. So we'll be able to see that in the sentinel cohort. Then obviously, we'll be able to build in the baselining period in the rest of the phase two as we fill up those cohorts one and two. Got it. Okay, makes sense, and besides achondroplasia, you've reported some preclinical data for hypochondroplasia as well. Can you talk about how you're thinking about expansion opportunities outside of achondroplasia and how that could develop over the next few years? Yeah, I think this first part of our phase 2 in terms of evaluating the safety at these different doses and initial efficacy will help us then essentially spearhead the hypochondroplasia phase 2 that we would want to run. We're doing it sequentially just because we think the dose information we're going to hear will help us design a more streamlined hypochondroplasia study. It'll likely be the higher dose we'll want to use in that study given what we know about the target. Got it. Okay. And then for NMIBC, you filed the IND, but you haven't announced that it's been cleared yet. Is that going to be something that happens pretty soon, or? Yeah, what we've guided to is we'll be filing before the end of the year. So it'll happen soon, yeah. Got it. Okay. Anything else we should know about both of these studies and just some of the milestones and how you're going to provide updates to investors along the way? Yeah, look, I think these are open-label studies. We're going to be having safety information as we get into next year, followed by 6-month efficacy on the achondroplasia side. We're talking about 3-month endpoints on the NMIBC. So I think what you'll see from us is an acceleration of data, especially as we get into these phase 2s and these other areas going into next year. Got it. Okay. Well, we're almost out of time. Maybe to wrap up, if you want to talk about key catalysts ahead that investors should be focused on over the next six to 12 months. Yeah, so we're going to be getting our first patient dose in achondroplasia. We're going to be getting an NMIBC IND cleared, followed by first patient dose there, and then that will really set some pretty rapid timelines for the readouts that we'll be guiding to when we get into next year. Got it. Okay, well, thanks for speaking with us today, Todd. Yeah, thank you, Maury.