All right, good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining us for TD Cowen's fifth Annual Oncology Innovation Summit. For our next fireside chat, I'm very pleased to have Tyra Biosciences here, and it's my pleasure to introduce Todd Harris, Chief Executive Officer. Todd, thank you very much for joining me. Thank you, Tyler. A pleasure to be here. Thanks for the opportunity to speak and, for that introduction. Of course. Before we get started, for those in the audience, if you have questions, feel free to email them to me at tyler.vanburen@cowen.com. With that, Todd, maybe we'll go ahead and start off with a general overview question for those that are less familiar with Tyra. Be helpful to hear you describe why Tyra was founded and your unique discovery process and SNAP platform. Great. So at Tyra, we're a- we are a small molecule precision medicine company. The founding was really around a group of structure-based drug design professionals, and this idea of using those tools to make a more specific FGFR3 inhibitor initially, and that's a really hard engineering problem to tackle. We built what we call our SNAP chemistry platform, really to tackle this. It's an in-house, rapid, iterative approach to structure-based drug design. So if you were to come visit us in Carlsbad, where we have our biotech labs and headquarters, you'll find some really lean, but highly competent groups that can do rapid crystallography in as little as three days. We do cell-based assays in-house, and we do in vivo in-house, and this allows us to just very quickly iterate and design precision drugs that are potentially best in class. Great. So we're gonna go ahead and start with oncology, with respect to the TYRA-300 program, that you just referred to, given the update later in the year. But maybe again, first, you could elaborate on TYRA-300, and more specifically, how it was discovered and how it's differentiated versus the other FGFR3 inhibitors out there. Yeah. So again, this is new chemistry built from scratch here at Tyra from our founding, and it was really around tackling two issues that we saw with current chemistry, the pan FGFR inhibitors that have been moving forward, and there was one specific drug, erdafitinib, that J&J has advanced into metastatic bladder cancer, where they've really validated and done an amazing job validating that FGFR3 is a very important target for that indication, both in early stage and in late stage. But the challenge with that chemistry as a pan FGFR inhibitor, you have certain toxicities that come along for the ride with some of the FGFR isoforms. So by building a potent FGFR3-specific inhibitor that spares FGFR1, we have an opportunity to reduce or spare hyperphosphatemia, which is a risk that needs to be managed because of its potential to lead to tissue calcification, and it's something that's seen really in the first few days of going on a pan FGFR inhibitor that hits FGFR1, to spare FGFR2, which with what we've seen from a FGFR2-specific inhibitor, Relay's drug, for example, is that it can drive a lot of toxicity associated with dry eye and eye tox, dry mouth and stomatitis, nail, hair, and skin tox that can be really challenging for patients. And then FGFR4, where you see diarrhea, bile acid accumulation in the liver and in the GI tract. So those are the things that we really wanted to spare, make a more tolerable drug that hits FGFR3, in the way that you want to get the, you know, the validated activity that's been seen with some of the pan FGFR inhibitors to date. Okay, that's helpful. So, as you mentioned, TYRA-300's in the clinic, the Phase 1, 2 SURF301 study has been ongoing for a little while now. You guys have both a Part A and a Part B, so it'd be helpful if you could elaborate on the rationale behind the design and where exactly you guys are in the SURF-301 trial at the moment. Yes. So we designed the study in two parts. Part A was to get to an MTD as quickly as possible, so it's really looking at tolerability, toxicity, AEs. Part B was to expand into the validated patient populations, the FGFR3 patient-positive patient populations. Part A, what we were looking for is, you know, is there... You know, what we wanted to avoid was any idiosyncratic tox, hoping to confirm there wasn't anything necessarily driven by FGFR3 that would be dose limiting. And given the way that we designed this drug, we knew that the next, you know, the next targets that were adopted with this drug will ultimately be the other isoforms, even though they were, they were spared the other FGFR isoforms. So we were hoping to move all the way up, maybe see some of the activity from the pan FGFR tox, and then basically move the dose down to get a really optimal FGFR3 inhibition while sparing the other isoforms. So we actually completed Part A at the end of the year. We actually completed it without getting to an MTD, but we saw what we want- what we wanted and needed to see, and so now we're fully engaged in our Part B cohorts. Some of these cohorts started enrolling fall of last year. We're still enrolling in these Part B cohorts, but the whole idea is multiple dose,... levels as well as dose schedules when you think about QD and BID, so that we can narrow down the optimal dose, the dose that's inhibiting FGFR3 and maximally sparing any of the other FGFR isoforms, so it can be best tolerated. Okay. And just to follow up on the Part A completion by the end of last year, you technically could not be hitting an MTD, but you could obviously still see some of the AEs from those other isoforms, right? Which wouldn't be terribly surprising, given the fact that you guys are so incredibly selective for three. Is that fair? Yeah. That's exactly the way I think about it. I mean, we saw what we wanted to see. That was sort of, you know, everything came largely on track, and didn't feel like there was a need to push dose any further. So, moved into the Part B, where we could explore multiple schedules, you know, dosing schedules that were lower than what we saw in Part A, to really maximally, yeah, to get to the optimal, dose, which is very, very important. You know, it's been a big focus of FDA, and it's a very important focus for a drug like this that's designed to be specific and selective. Okay. What's the latest in terms of any sort of granularity you can give us with timing for the initial data update from the 301 trial, and what you hope to see from that readout? Yeah, so we're planning for an initial data cut to be shared in the second half of the year at a major medical meeting. Yeah, this will be the first disclosure of clinical data, so it's obviously a big, big event for us. And yeah, we'll obviously have completed Part A, so that information's available. Part B, we've got some more mature cohorts, but we're still enrolling in Part B. So if you think about, there may be some data that is less mature when you think about those cohorts. But the goal is really to, you know, to showcase, our, you know, where we're at on our path to choosing the optimal drug and get us ready for, launching multiple phase 2s. Our first phase II is actually gonna be submitted as an IND the second half of this year, but we're planning on additional phase II's coming out of the work that we'll be sharing. Can you talk a little bit more about, just the competitive landscape and ultimately, what you believe TYRA-300 needs to show in terms of both efficacy and safety to be successful, in FGFR3 mutant bladder cancer? Yeah. So let's start with where I think the most information is available, and that would be in metastatic bladder cancer with Erdafitinib, which is really, I think, a great benchmark. In terms of efficacy, you know, its ORR was 35%, but a lot of patients do see a lot of clinical benefit with stable disease. The real limitation with that drug, though, has been a lot of patients come off due to tolerability in the first few months. It's got a pretty limited PFS of around 5.5 months. So what are we looking to achieve? Well, we wanna hit similar, if not better, efficacy in terms of initial ORR. We don't, you know, the goal with a drug like this is not necessarily to maximize ORR. The goal is to maximize PFS. And so a similar, you know, if not better, ORR, you know, tells us that we're hitting the target, the way that we want. And then, really, the tolerability is what we're looking, you know, to carry the day with a drug like this. Allowing patients to be able to stay on drug for longer, achieve that, you know, clinical benefit, is a, you know, is a big goal. So that's what we're looking to kind of pull out of initial data, is, that dose where, you know, similar if not better initial ORR, and then better tolerability. And because there aren't well-validated PD markers for FGFR3, we really have to look at enough patients to kind of get a relative handle on that, you know, ORR tumor shrinkage as the initial marker. But we are trying to obviously build out the PD markers as well as we go. What sort of improvement in duration of response or median PFS do you guys believe you need to show relative to erda? Yeah, I think it's important to highlight that, you know, you don't really get solid numbers on PFS and durability, I think, until we, you know, we get right patient, right dose for a lot, you know, for a relatively good number of patients. So we wanna be a little bit cautious about how much is read into this initial data set, because really, for us, it's about tolerability and, you know, at a dose that we know is, you know, oh, an ORR, you know, similar if not better. Long-term, though, we think beating the 5.5 months PFS is absolutely feasible, with a drug that's well-tolerated, and so it's really, you know, showing an improvement there. Would be the goal as we move into phase II, and then ultimately setting up, you know, the right, confirmatory study or phase III study to take it the distance in metastatic urothelial. Now, there's a significant read-throughs beyond metastatic in NMIBC, intermediate-risk NMIBC and achondroplasia coming out of this data as well. So I wouldn't wanna, yeah, I think it's important to highlight how even that data that I just described, you know, gives a important read-through on some pretty big opportunities outside of metastatic urothelial as well. Okay. When thinking about the recommended Phase 2 dose selection, my understanding is that you're collecting biomarkers. It'd be helpful to hear you speak a little bit about those and how that's going to help inform your RP2D. ... Yeah, two, I think two key things that we're doing. One is leveraging the Olink platform to look at a number of different serum protein-based biomarkers. Others have looked at these with pan FGFR inhibitors, so it sort of gives us a unique window to say, "You know, are we seeing something similar or different with a selective?" And cell-free DNA, of course, looking at, you know, early, you know, looking at correlative markers with tumor shrinkage and what's happening to DNA is another really important biomarker that we're tracking as well. Okay. And as we think about the future Phase 2 program that you alluded to, what indications... You spoke about several indications beyond just metastatic, but what indications do you expect to prioritize in development, and how large is the FGFR3 mutant bladder cancer opportunity? Yeah. So there's really three very important sort of next step phase II. And then, beyond there, I think there's additional opportunities. But we're prioritizing obviously the metastatic urothelial you know will be a... That's the population we're studying today, so continuing that into phase II with SURF301. But then opening up NMIBC, and specifically intermediate-risk NMIBC, where there's a you know a majority of patients are FGFR3 positive. Erdafitinib has demonstrated some very compelling validation with its use as both an oral and as you know as a TAR-210 pretzel via instillation. In both instances, what you're seeing in a marker lesion study is that it can be chemoablative when you inhibit FGFR3. So we know within a few months, you see, lesions essentially, you know, see complete responses, and this is upwards of 80%-90% of lesions. So FGFR3, you know, inhibiting that is an excellent target, and so demonstrating with TYRA-300, you know, with a tolerable dose in the NMIBC setting, we think is just a really big opportunity. Erdafitinib is not, or J&J is not pursuing erdafitinib as an oral because the toxicity is essentially too much. And so they're looking at this local delivery approach with the TARIS platform and the instillation, and I think that's really evidence that, you know, if they could have, they would have on an oral. That's the opportunity with an FGFR3 selective, is to go, you know, potentially get a well-tolerated oral solution here that gets the kind of responses that they saw in their phase 2. That really then opens up an interesting phase 3 path for a confirmatory study using an oral selective FGFR3 agent. And then finally, achondroplasia. Here, it's even potentially a lower dose. I should mention with NMIBC erdafitinib, where J&J used a lower dose of erdafitinib to see those high CRs, so we anticipate it could be a lower dose for NMIBC, and then even a lower dose in achondroplasia. In achondroplasia, the target, the alteration is FGFR3, and we think we can, you know, engage it with a great therapeutic index window, to optimize a potential best-in-class drug for that patient population. Okay, perfect segue into ACON. So the IND submission is guided for the end of the year, I believe, assuming that's still on track. And maybe you could just describe how you plan to take the information learned from the SURF301 study and utilize that for essentially to get a head start or a jumpstart on ACON. Yeah. So, you know, because we started moving into the Part B cohorts, you know, in the fall, you know, we've been able to have a lot of patient experience now with TYRA-300 over, you know, over long periods. And we also have done some work with healthy volunteers, and then we've also been doing all of the necessary work around chronic tox, six- and nine-month tox. All of that data really comes together, you know, in what we anticipate for our IND submission in the second half of the year, and then spelling out, you know, a really thoughtful approach to move initially into sentinel dosing in kids, and then to select a dose to move into a study with pivotal intent. So, you know, we're feeling really great about, you know, where we're at today. You know, you don't want to hit an IC90 in this patient population, which is different than oncology, so we know it's a lower dose. We think the dose is, you know, probably more up to about half the oncology dose, where you might be hitting about an IC50, is sort of the right target to go up to. No one's really been able to explore FGFR3 inhibition up to that amount. BridgeBio is in this indication with a pan FGFR inhibitor, and they're targeting about 1/6 of the oncology dose. So really, we anticipate that just tickling FGFR3 there and really getting the right level of inhibition is the opportunity we have with an FGFR3 selective. Yeah. The patients you guys have enrolled in the bladder cancer study, none of them have been young enough for the FGFR3 inhibition to really impact their growth, right? Is that fair? Yeah, that is fair. Okay. All right. So I guess, you know, the move or the selection of achondroplasia as an indication of interest is not terribly surprising, given the PROPEL 2 data that we saw from BridgeBio's infigratinib, which you mentioned. So it'd be helpful to just hear your latest thoughts on that program, especially given the, I guess, 18-month data that we're gonna see early next month, and how you guys plan to differentiate? ... Yeah, I think, you know, as I mentioned, you know, our, you know, based off of the preclinical models, and I think when you look at really the clinical dose that they've chosen, we do think they're, you know, suboptimal relative to the target. So, you know, what's the goal here with these kids? I mean, the goal is ultimately addressing the important clinical sequelae that can come. Individuals with achondroplasia, you know, they face a lifetime of, you know, potential pain and surgery, largely around issues with the spine, limitations in reach, and other clinical sequelae. So that's the end goal. Then, you know, the surrogate endpoint that the FDA, and I think, you know, the clinical development community has aligned around, is looking at annualized height velocity as an important surrogate to say, you know, "Have you addressed the alteration, the overactive FGFR3 appropriately?" And it would be, you know, expected that if you had the right tone of FGFR3, if you lack the alteration, kids, you know, between ages 2+, are gonna grow about 7.6 centimeters per year. But kids with achondroplasia, with active FGFR3 expression, you know, they're growing about 4 centimeters per year. So this gap that you're looking to make up, you know, BioMarin's been able to show about 1.5 centimeters of incremental improvement. That's... You know, maybe it's, it's one-third of the way of what you're really looking to, to restore in terms of this surrogate. You know, BridgeBio, it's, it's gonna be, really helpful to understand, are they at that level when they share that 18-month data? Are they significantly more? If you look at the patient population they treated, you know, our estimate is, and I think BioMarin highlighted this last week as well, is that they're probably... You know, this is a population that on Voxzogo probably would've grown about 2.4 centimeters per year. So that's the real benchmark to look at when you see the 18-month data. And, I think that's, that's, something that, we think that there's an opportunity to do much, you know, much better. When you get an average patient population, BioMarin, you know, using CNP, recently showed in the idiopathic short stature population, they could take kids from what would've been a baseline from 4 centimeters to about 8.5 centimeters at 12 months. I think those are the kinds of benchmarks that show you you're really hitting the target right. I think with FGFR3 inhibition, that should be the goal, that should be the target, is the several centimeters improvement in AHV, which then ultimately should read through to the clinical benefit. Okay, that's very helpful. And as you think about the phase II achondroplasia trial, what do you envision as the design for that trial? Is there a specific... In addition to that, is there a specific age range that you have in mind in terms of the patients that you'll be enrolling? Yeah. Initially, we're gonna be looking at 5-12. That's the most linear, you know, AHV range, so it helps us in dose selection. But from there, you know, as we identify dose, we wanna expand that out, of course, into age 2+, and ultimately go into, you know, newborns, I think where there's a ton of potential clinical benefit. We'll stage that out. So for this initial study, we're gonna look at some sentinel dosing upfront just to get the, you know, the dose escalation right, and to choose what we would consider, you know, sort of the best and most optimal dose than to go into a phase III. So I think it'll look like that. It'll look like, some sentinel dosing upfront, selection of dose, and then moving into a, a pivotal study. Okay. When could the Phase II start? So we're submitting the IND here in the second half of the year. So, assuming it's, you know, positive read there, and then getting sites up and running, we'll be moving forward as quickly as we can. Okay, great. So, again, naturally, we spent most of our time on TYRA-300, but you guys have other candidates in the pipeline that you're working on that are developed from the SNAP platform. So it'd be helpful if you could provide an overview of that, and perhaps highlight what's coming next. Yeah. So a lot of our focus with the SNAP platform has been just building out expertise in the FGFR family. We have TYRA-200, which is positioned for cholangiocarcinoma, and it's a drug that hits all those acquired resistance mutations that have been seen in patients with cholangiocarcinoma. That's about 2/3 of the patients that go on in a first gen FGFR inhibitor see those. So pretty significant prior FGFR inhibitor-treated patient population we might be able to address. TYRA-430 is a molecule that we're starting to talk a little bit about, and it's something that I think you can see more information from us here. But it's hepatocellular carcinoma-focused, where we see FGF19 playing a role, and FGF19 does bind and activate FGFR4 and 3. 3 is a bypass mechanism, so using our expertise there, we've got a really interesting program moving forward in IND-enabling. You know, and then I think more to come. We remain very, very active in making small molecule precision potential drugs in the FGFR space. Okay, great. With that, we're up on time, but I'll wrap with a question I often ask in closing: What, what aspect of the TYRA story is most underappreciated by investors right now, Todd? I really think it's the size of the opportunities. Some people come and say, "Hey, I really like achondroplasia." Some people come and say, "I'm really interested in intermediate-risk NMIBC or metastatic urothelial." The reality is all three of those, they're really, really big opportunities with one drug. And in addition, you know, we've made all of our molecules from scratch, so I think people, you know, shouldn't count out all the things that we potentially can do with our discovery platform going forward. Okay, awesome. Todd, thank you very much for your time. Thank you, Tyler. Always nice chatting. Thanks to everyone for logging in.