Perfect. Thank you so much. Good morning. Welcome to Barclays Global Healthcare Conference in Miami. My name is Peter Lawson, and I'm one of the biotech analysts here. I'm really pleased to have up on stage with me management from Tyra. So we've got Todd Harris, CEO. And I'll open it up with a series of questions, I guess, initially around achondroplasia and kind of the IND filing and where you're standing, really, for how many patients you control for each dose cohort. Yeah. So what we've announced publicly this year is we'll be submitting our IND for TYRA-300 and achondroplasia. It's a really exciting milestone for us. We opened up this opportunity last year based off of some really exciting preclinical results. And then, of course, we've been active in a phase one now for over a year in our SURF301 study with TYRA-300. So that's been very informative for the window of opportunity we think we have with this compound. Really, the goal here is, with an FGFR3 selective, we think we can hit the target, FGFR3, which is the altered gene in achondroplasia, appropriately, and make a significant impact on the outcome of kids and individuals with disproportionate short stature dwarfism or caused by achondroplasia, which is the G380R mutation in FGFR3. Gotcha. And then, as we look at, say, peer trials, etc., would you kind of mimic something like that? So you'll have 10 patients per cohort, like BridgeBio, or? Yeah. Great question. There's a few examples of individuals doing development here, first with BioMarin. They have the accelerated approval with VOXZOGO, Ascendis, which is a once-weekly injectable, and then, of course, BridgeBio, which is the other oral pan-FGFR inhibitor. In terms of dosing and development, Ascendis is probably the best example of how we'd like to think about moving forward here. Their sentinel dosing was relatively quickly. They moved up through doses to confirm safety, and then after sentinel dosing, went into more comparative readouts, as opposed to BridgeBio, that had a much longer sentinel dosing period. So we too, we're going to look at sentinel dosing. That's really focused on making sure we move safely up through dose cohorts. We may backfill at the higher cohorts where we anticipate having efficacy just to prioritize making sure kids are getting an effective dose. But we'll look at leveraging that sentinel dosing to move into placebo-controlled, potential pivotal cohorts. And so those would be obviously bigger than 10 patients. But in the sentinel dosing, I think of the maybe a little bit bigger than some of the sentinel cohorts that Ascendis saw, maybe a little bit smaller than what BridgeBio did, as I think their last sentinel cohort was about 12 patients. But across doses, I think it'll give a really meaningful input around, first and foremost, safety, but then signals of efficacy when you look at biomarkers and AHV. Gotcha. And then, just as we think about the age range, is that going to be similar, different to peers? Kind of how should we think about that? Yeah. Initially, FDA is pretty clear. With companies like us, they want to start by12, and then you can open up two plus, and then you can open up at lower doses. We'll follow that path, starting with the five plus age range and then expanding into additional age ranges from there. Gotcha. Is there anything else that we should be thinking about, differences or similarities with other trials out there when we start comparing and contrasting? I think there's been a lot of great work done, and we can learn from the experience and work from others to go fast and ensure safety. That's really what our goal will be. I think recruitment speeds have sped up in the last few years. If you look at Ascendis, they were very fast enrolling in their phase three. I think that's a reflection of momentum with families and physicians seeing that interventions are having an effect, and so it's worthwhile exploring clinical studies. We have this window, I think, while there's still many investigational products to think about moving our development plan forward quickly, especially if we're going to be having placebo controls, which it appears the FDA continues to guide all companies towards that. Even though BioMarin has an accelerated approval, that's not yet confirmatory. As long as that's the state, I think FDA will want placebo-controlled studies. It's important for us to move quickly, and we're obviously leveraging the experience of others to do that in our own program. Gotcha. What's the starting dose in achondroplasia versus oncology? Yeah. We're increasingly, I think, understanding a pretty good picture here based off of the preclinical models, based off of clinical experience. In FGFR3 inhibition, you don't want to cover the target as much as you would in oncology. An AUC90 is sort of the rule of thumb. You You think about constant AUC90 coverage in oncology. And the reason is that when you look at what happens with kids that go on oncology doses that still have open growth plates, you see a significant amount of growth, anecdotally. Some kids might grow 20 centimeters per year, when the average should be about 7.6 centimeters per year. So that's rapid growth, and it sometimes comes with complications like fractures and SCFE. So AUC90 is not the target, but we think an AUC50 is probably a reasonable target from what we've seen in preclinical models. I think there's still a lot to learn here. We generally would characterize that as up to about half the oncology dose. For reference, infigratinib's oncology dose was 125 mg a day. Their dose that they're moving forward in phase three, it's about one-seventh of that dose. That was really restricted by hyperphosphatemia and FGFR1 inhibition that seem when you go above that based off of their phase one from what's been shared publicly. That's really the opportunity we see with an FGFR3-specific, is exploring this sort of up to AUC50, this one-seventh to one-half the oncology dose we think can really optimize FGFR3 inhibition. That should get reflected in AHV. But more importantly, we're looking at the clinical sequelae, the long-term outcomes, proportionality, and a number of other metrics, including pain, that really can be improved upon by hitting the FGFR3 target the right way. Gotcha. Those kind of lower doses, do you think that kind of helps mitigate any hyperphosphatemia, or? Yeah. The team at QED, BridgeBio, has been pretty clear all along about defining the safe range where they could avoid hyperphosphatemia. And it's a lower dose and lower by a pretty significant amount than the oncology dose. And we think that, like I said, moving up to something that may be in the range of half the oncology dose could be really the right amount of target of FGFR3 inhibition from what we see preclinically. Okay. Is there a balance and angle between that and fractures? Yeah. I mean, I think the fractures are clear when you get to constant AUC90. But I think there's good evidence preclinically that you can move quite a bit up from where BridgeBio is today with one-seventh of the oncology dose. Is that kind of dose level three thing, or? For us, dose level three, four? Yeah. I mean, I think with the SURF301 study, we started at a 10 mg dose. What we've tried to educate individuals that's important is in the preclinical models, you actually see toxicity from FGFR3 because you have open growth plates in rodents throughout life. And that's really informative because it's around that level of activity of FGFR3 that you sort of start at one-sixth of that dose in an oncology study. So that's sort of the range sort of up to that point that we're talking about exploring here. It's not going to the full oncology dose, but it's going to where you start to see effects in the animal models from FGFR3 inhibition, which is actually a tox signal in chronic dosing because of the bone effects when the growth plates are open. Gotcha. Perfect. Thank you. How far behind do you think you are with BridgeBio? Yeah. BridgeBio took a lot of time in their sentinel dosing. And I think our goal is to work on a plan that allows us to move safely and quickly through the sentinel dosing period. That, I think, makes up a lot of ground for us. They just didn't started enrolling their phase three. We're not going to be enrolling a phase three this year, but we're submitting an IND. We want to move pretty quickly through sentinel dosing. And we're looking at leveraging that sentinel dosing for a pivotal cohort that could move quickly and make up quite a bit of ground relative to where others are at. Gotcha. Thank you. And I guess the bar for that in terms of growth velocity, what do you want to see? Yeah. Kids with achondroplasia, through natural history studies, it's been well established they grow at about four centimeters per year if you look at age two plus. And you can compare that to the Merck Manual for kids age one plus who are growing about 7.6 centimeters per year that don't have achondroplasia. So that gap, call it 3.6 centimeters, four centimeters, I think is target. BioMarin's, their long-term studies sort of show around 1.5 centimeters. So they're not making up this gap of potentially four centimeters. And that's really the target we'd like to see. And I think you need to measure that out at 12 months. The six month AHV usually overpredict what you're going to see at 12 months and then continue to look at that at month 24 and beyond, which BioMarin is starting to do and highlight that they've got consistency. It's important because growth hormone actually has a really nice AHV number when you measure it, but it's 8.6 centimeters in the first year. But you see a massive attenuation back to four centimeters and even below. So that long-term final height really isn't of any significant benefit with that agent. So it's important to follow it out. But yeah, our target is getting to physiologic normalcy in terms of that 7.6 centimeters that could be measured at 12 months, 24 months, and beyond. Gotcha. And then quality of life measurements, kind of what are you tracking? I guess pain's obvious, but anything else? Yeah. Yeah. Yeah. That AHV number is really just a surrogate for what we're really trying to accomplish here. Some of the more important clinical sequelae you see that lead to medical complications are pain and surgeries, often associated with stenosis in the foramen magnum at a young age, but stenosis in the spine at older ages. There's a growth plate essentially there in the spine that's widening that spinal canal. So being able to start to detect that radiographically is, of course, one thing that we're looking at just to get a signal of improvement maybe earlier than waiting for long-term outcomes in pain and surgery. The long-term outcomes are going to be very important. Gotcha. I know Bridge is starting a trial in hypochondroplasia. Is that something you'd follow or replicate or other areas we should think about? Yeah. I think it's important to highlight too, I mean, BioMarin's recent R&D day this week. They continue to push on how exciting the growth expansion opportunities are here in skeletal dysplasias. Hypochondroplasia was a first step for them. It appears to be a first step for BridgeBio. It's something that we're also looking at as a next step. Importantly, in hypochondroplasia, the mutation, while it's a more milder phenotype, the mutation actually occurs in the active site. So all of the small molecule inhibitors, TKIs, they actually lose about three to five fold activity. That means you need to dose up more to have the same level of activity, even though that phenotype is more mild. So you see that with in QED, they looked at a higher dose in their hypochondroplasia model to get an effect. And so I think that speaks to the strengths of an FGFR3 selective as well because you're going to want to be at that highest safe dose, I think, to have the best effect in this condition. Gotcha. Thank you. And then I'd love to pivot it over to the oncology side of things. So in FGFR3 inhibition in bladder cancer, just the strategy around dosing and development in 301? Yeah. So we've been in this study for over a year. Things are going really well. We designed this study with a part A and a part B. Part A is all-comers, and it was designed to move very quickly to identifying an MTD. The strategy here has always been we hope to see the things you'd want to see. We'd want to see exposure at increasing doses. Ultimately, we didn't want to get surprised by idiosyncratic tox, even FGFR3-limiting tox, but rather be able to dose up high enough to kind of our the next targets on the list, which are actually the pan-FGFR targets. The things you see in that first window from pan-FGFR activity is hyperphosphatemia. So part A was about trying to push the dose up to there and then back off of that dose to where we've fully optimized FGFR3, and we can eliminate or reduce toxicities that the pan-FGFR inhibitors see based off of our selectivity. So part A is we've largely rounded out the goals we had in that study, and we are backfilling in these multiple part B cohorts. And to just put a fine point on that, we really want to fulfill the types of guidance Project Optimus has given, which is how do you choose the safest dose that is effective? And there isn't a clear PD marker for FGFR3, so we have to look at things like efficacy in the right patient model, focus a lot in our solid tumor FGFR3-positive in urothelial, for example, where erdafitinib has well-established benchmarks. And then look at efficacy with optimized safety based off of choosing that right dosing parameter. So we've been through several B cohorts. It's going very well. We continue to enroll in these B cohorts really to try and fulfill this objective around Project Optimus. And I think each cohort, we sort of target about 10 patients and really try and enrich in this FGFR3-positive urothelial patient population. Perfect. Thank you. Maybe some finer questions just around where you are in that dose escalation in part A, so which cohort? Yeah. Part A, we've largely gone through the objectives of all the doses we wanted to test. Gotcha. Okay. You don't need to push the dose any higher in part A. It's like you're happy where you are? Yeah. Success for us has always been about not taking an MTD as our recommended phase two dose because we feel like FGFR3 shouldn't be driving as an MTD, and therefore, we don't need to go to the higher doses where the next targets we hit, even though we have about an order of magnitude separation, the next targets we hit are FGFR1, FGFR2, and FGFR4. And that's well-understood tox. So if we can see that at the highest doses, that gives us a really good benchmark of backing down to reduce it and really focus on full FGFR3 inhibition. Gotcha. Is discontinuation rate something you have to monitor really to work through what that best dose is, and what is that kind of best dose? Yeah. When you look at pan-FGFR inhibitors, discontinuation rates can be upwards. I mean, reduction or discontinuation rates can be upwards of 70%-80% with some of these agents. So it happens a lot. And it's because of a multitude of factors that it includes the pan-FGFR activity that you can see from FGFR1 and two. So obviously, we want to minimize that and optimize for a well-tolerated drug. Gotcha. How low can you get for that discontinuation rate where you still see efficacy? What's a meaningful bar? The data will say. I mean, I think we want to go through a number of patients to really understand that. But you see in the pan-FGFR inhibitors, this ranges, I think, from 20% upwards to above 50% in terms of discontinuation. Gotcha. Perfect. And then that part B, kind of is that mostly metastatic urothelial cancer patients? Yeah. It's FGFR3-positive solid tumors, but we are increasingly focused on a population of metastatic urothelial based off of the centers that we're going to and because I think that's going to be the easiest benchmark based off of the erdafitinib experience to sort of compare efficacy, know that you're at an efficacious dose, and optimize tolerability. And one thing we've really guided to that's important is our goal here is to meet, if not exceed, just the initial response rate that's seen with erdafitinib. That's about a 35% response rate every time they've measured this. But do so with a more tolerable drug because erdafitinib's PFS in the late-line setting is about 5.4 months. And a lot of that actually gets driven by patients coming off of therapy despite having a partial response in those early months due to tolerability. So if we have a similar response upfront and improved tolerability, we think that can translate to meaningful improvements in PFS and OS, which is really the endpoint that matters here. Gotcha. Okay. So that 5.4 is, you think, very achievable? Yeah. I think a well-tolerated drug, engaging FGFR there, it has an opportunity to move that out quite a bit. Gotcha. Thank you. Where should we see that data? Is that kind of like an ASCO thing, or? Yeah. So we're going to be sharing the first cut of data. And I think, again, the thing to focus on is benchmarking response relative to erdafitinib and looking at tolerability. And that data will cut this year and share. We've got it at a major medical meeting and expected to be in the fall. Okay. Perfect. And that's going to be part A and part B, or how much data? Part A and part B. Okay. How many patients should we expect to see? As I mentioned, for the part B cohorts that are filled out and filling out, we're really targeting 10. And then obviously, for the part A cohort, this is a pretty standard three plus three design. So I think it will be a reasonable number of patients. For safety on efficacy, it might be a little bit more constrained because you're going to want to focus on right dose, right patient in that part B cohort. Okay. And recommended phase two dose, I can't recall. Do we know that yet, or? Our goal here is to get there and really fulfill or try and fulfill with FDA the Project Optimus-type guidelines they've given. So hence the reason we're doing these multiple part B cohorts. I think we'll have a really good idea as we're going into this year what the dose range will be. And it's really about filling out the right level of patients in these cohorts that can say we've actually selected the most tolerable, efficacious, or safest efficacious dose. So I think we'll be well on our way this year to figuring that out, especially knowing the range of doses. Gotcha. And then when we look at safety, what we hone in on, discontinuation rate and hyperphosphatemia, or other things that we should be thinking about? The nice thing about so hyperphosphatemia is helpful because you see it in the first 30 days. You see it in the first eight to 15 days when you're hitting FGFR1. FGFR2 is a more chronic tox that builds over time. It's a little bit harder to see. And you could look at Relay. There was a good example of this with their FGFR2 specific. They were able to get really high doses in that 30-day period by sparing FGFR1. But as they went on with that drug, they saw that FGFR2 on-target tox for them, tox really accumulates. So it'll be important to spare hyperphosphatemia in that 30-day window. But then it'll be important to look at months two, three, four around the FGFR2 tox. And that's often what drives dose reductions in patients in discontinuations. It's actually what you get is stomatitis, mouth sores. You get your nails falling off. You get this redness in your hands, feet. There's some eye tox. So all those things make it uncomfortable for patients to stay on drug over the longer periods of time. And that's largely now been connected to FGFR2 activity, which we also do spare. Okay. Do you need to think about different dosing schedules, or you're fixed there? Is it daily, etc.? Yeah. In our preclinical models, we showed that QD, BID dosing was very similar in efficacy. Those are sort of the standard things you think about in a phase one in terms of dosing schedules. And we have indicated that we're looking at dosing schedules here. Again, this is all in the spirit of making sure that we got the most optimal dose. Gotcha. Registration strategy, is that a kind of head-to-head that we should be thinking about, or? Yeah. I think with erdafitinib's full approval demonstrating superiority to chemo, which is a really exciting outcome that occurred this year, it sort of sets us up to look at this second-line post-PADCEV setting that's pretty wide open and demonstrate improvement over erdafitinib. And so that's the way we'll think about it designed. FDA's guidance more recently has really encouraged individuals to enroll a pivotal study but potentially look at interim endpoints like PFS that could get an accelerated approval on your path to looking at the more important OS endpoint. So a study like that is something we'll look at for the late-line setting. Perfect. Thank you. And then I guess in the last minute or so just on non-muscle-invasive bladder cancer, kind of just where you stand there, especially, I guess, in light of other data emerging within that space, kind of what the real bar is for you? Yeah. It's really exciting. I mean, a lot of momentum around CG Oncology. People are starting to wake up to just how important this space is. And so NMIBC, the five-year survival's really good, but the standard of care today is really lacking. BCG is one of the most frequently used medications, but there's a massive shortage. And BCG, or chemo, or even surgical removal, all of these involve catheterization and a procedure that's not necessarily comfortable for the patient and can have some really long-term complications and discomforts and requires multiple repeat treatments and visits. So I think CG Oncology will still be that, a procedural solution. J&J is looking at putting erdafitinib in a drug-eluting device and installing it every three months in the bladder. So I think these are exciting. I think one of the most exciting things that happened this year was seeing erdafitinib's oral data. Its efficacy showed 70%-80% complete responses and recurrence-free survival in intermediate risk and high-risk NMIBC. But patients struggled to stay on drug past three months for tolerability. And so I think if they could have taken that orally, they would have, but it's not going to move forward, even though they tried a lower dose and it was very effective. That really shows the opportunity for us, a well-tolerated oral you could look at potentially a lower dose than in the metastatic setting. And I think we would really stand apart in the space, which is a really big number of patients who I think are looking for a better solution. FGFR3 positivity is more than 50% in this patient population. We're talking about hundreds of thousands of patients there today looking for better solutions. Perfect. Thank you so much. Pleasure to chat with you. Chatting with you, Peter. Take care.