The last day of Bank of America Healthcare Conference here at Vegas. My name is Hao Shen. I'm associate of Geoff Meacham, who is the senior biopharma analyst at Bank of America. Today, it's my great honor to have Todd Harris, the CEO of Tyra Biosciences. Todd, welcome. Thank you. It's nice to be here. Maybe, you know, just to kick off the conversation, could you maybe just give a high-level view of Tyra, the company? Yeah. Tyra Biosciences is a company focused on precision medicine. We make small molecules. We actually make them from scratch. We do structure-based drug design. Our unique approach is our SNAP chemistry platform. It's a rapid, iterative, in-house capability that we've built to make really differentiated molecules. We've largely focused this on FGFR biology. Our lead asset is TYRA-300. It's the first FGFR3 selective inhibitor to make it into the clinic. We're in a phase I right now. We have other assets as well behind it. We can talk about that. Sounds good. just to dive a little bit deep into your SNAP platform, how would you say it's sort of differentiated from other platform developing small molecular inhibitors? Yeah. Structure-based drug design, you're looking at structure activity relationships. That involves crystallography or whatever approach you wanna use to see how your ligand or molecule that you're designing binds to the protein. Conventionally, you know, protein crystallography is something that's done sporadically and maybe may take several months. This is an in-house capability we built so that on the order of as little as 3 days, we can take brand-new molecules that arrive in our lab in Carlsbad and mint a fully crystal structure. That allows our chemists really detailed structure information on each of the analogs of interest that we wanna look at. It's really important in FGFR biology because the FGFR isoforms, 1, 2, 3, and 4, they're all important in a variety of different conditions. When you wanna hit one of them, the active sites are nearly identical or in fact, are identical in the first cell of the active site, and then you have to look at more subtle changes outside of that. We leverage crystallography across all of those isoforms with our in-house capabilities to look at detailed differences and design more selective molecules. We couple that with two other functions that we prioritize in-house. One is our cancer biology and cell biology group with a ton of cellular assays that give us on-target and off-target information, and then an in vivo group as well. Awesome. That's very helpful. Let's dive into your lead asset, TYRA-300. Kind of exciting development. You have started the phase I. Maybe let's get one step back. Could you maybe provide just an overview about TYRA-300 and how it's sort of differentiated from other FGFR inhibitors? Yeah. TYRA-300 is an FGFR3 selective drug. There are 4 approved pan FGFR inhibitors that equally hit FGFR1, 2, and 3 that are on the market today. The key here is understanding what the limitations are of a drug that hits all these isoforms versus one that might be selective. We know from the on-label adverse events and AE tables of these approved drugs that the majority of patients on oncology doses will get hyperphosphatemia, which is driven by the FGFR1 tox. FGFR1 is in the kidney-regulating phosphate. That leads to the need to monitor your blood, go on phosphate binders, and it could lead to tissue mineralization. One of the more debilitating chronic toxes comes from FGFR2 tox. What you start to see is, your fingernails will disfigure, fall off, and it's incredibly painful for patients and often leads to dose reductions. You get these really bad mouth sores as well, and that's 'cause of FGFR2's activity, appearance in the glands, and you see that in the preclinical tox models. FGFR4 has some GI tox and liver tox as well. If you could make an FGFR3 selective drug, of course, you could avoid those toxicities. The opportunity for an FGFR3, because of its driver in bladder cancer and skeletal dysplasias, there's a ton of unmet need that you could address if you could design one of these molecules. It's a very hard profile, one that TYRA-300 is really one of the first... It is the first to make it in the clinic that achieved that. We see a ton of promise by being able to selectively hit this target. I think, you know, potential safety differentiation would be, you know, one of the key advantage of TYRA-300. Could you talk a little bit maybe also about, I think you have some data showing it's also sort of works in FGFR resistant kind of preclinical models. Yes. Great point. When the other key limitation of those pan FGFR inhibitors that are on the market today is all of them have a gatekeeper liability. Gatekeepers are mutations that happen in the back pocket of a kinase, the active site of the kinase domain. Typically, the first resistance mutation that crops up if you have a drug that is using the back pocket for binding affinity. We've seen it in EGFR. We've seen it in RET. We've seen it in ALK. Just about every target has had this gatekeeper motif arise. If your drug is accessing the back pocket, it has the liability. We designed TYRA-300 to avoid the back pocket structurally. As a result, we have near equal potency whether or not you have this gatekeeper mutation. It shows up in the clinic, in patients with bladder cancer. The limited data that we have suggests maybe 20%-30% will have this gatekeeper mutation. The number one reason that patients are coming off of therapy actually tends to be the tolerability issues, though. Makes sense. phase I study is ongoing. Could you talk about the design of the study and just general how it's progressing? Yeah. We designed the study in two parts. There's a part A and a part B. Part A is all comers. As we move up in doses, it's a 3+3 design, and it's pretty standard. We're trying to get to an MTD as quickly as possible. Part B, we're looking at FGFR3 positive patients and starting to look at PD and efficacy. We're able to, as soon as we clear a dose in part A, move into those selected patients in part B. We're gonna be looking at multiple doses, one, to fulfill Project Optimus, but two, because, if FGFR3 doesn't lead to dose-limiting toxicities, which, you know, to date, we don't think it would, it may be the other FGFR isoforms, and therefore, we don't wanna overdose, and lead to, you know, tolerability issues when we can hit FGFR3 just as well at potentially lower doses than our MTDs. That gives us a chance to balance the efficacy safety window we think we can achieve. Awesome. In terms of data release strategy, you know, were you thinking maybe some interim analysis possible, or maybe you would more prefer to, like, release the mature data, which can tell sort of the whole story? Yeah. We feel really strongly about this, that, the right thing to do, as a company and quite frankly, for investors, is to wait for a really mature data set from our phase Ia phase Ib study. You know, splashing out a little bit of data here or there, we just don't think it's gonna tell the full story of what we're trying to achieve with this study. We haven't given guidance to date on when we anticipate the full data set being available, but, we have let folks know we're gonna wait for the data to mature. I think one caveat to that is, we'll talk about achondroplasia, that's an area where we anticipate the dose being lower, which means, you know, we start to see a lot of that data on the phase I portion pretty quickly. The oncology data is not really as relevant there 'cause it's more of a lower dose PK exposure. We think that's gonna be relevant. Certainly that's information that's helping us with the design and planning for our achondroplasia study, which we plan to kick off next year. Awesome. Let's jump to the achondroplasia plan. You guys expanded TYRA-300 to achondroplasia this year. Your competitor have showed a promising data, sort of serve as proof demonstration of the FGFR inhibitor in this indications. Could you talk a little bit about your thoughts of sort of expanding the TYRA-300 to achondroplasia and how it's differentiate from, you know, other competitors' FGFR inhibitors? You bet. First off, I, you know, I wanna commend companies like BioMarin and BridgeBio and the patients and investigators that have done those studies, 'cause it's been a really exciting few years for kids with achondroplasia, starting with the BioMarin approval. I think the data there highlighted that there's some benefit in terms of the surrogate of annualized height velocity, and, you know, kids and their parents are starting to see that benefit on the market today. What was exciting about BridgeBio's recent data is I think they, their cohort five really gave this indication that the headroom, you know, or the kind of max benefit Voxzogo was getting to, that we can actually do better. It started to hint that by just direct FGFR3 inhibition, you might actually get to average height velocity in kids with this condition. You know, kids with achondroplasia from age 2 to 10, they grow 4 centimeters per year. Kids without achondroplasia are growing on average 7.6 centimeters per year. There's this big gap, and it wasn't necessarily thought that you might close the gap from the, from the BioMarin data. BridgeBio didn't close the gap either, but it's showing that with FGFR3 inhibition, they're kind of on the dose response curve you could get there. BridgeBio's decided to not dose above cohort 5 from their public disclosures, and that makes sense 'cause they are a pan FGFR inhibitor. You do have FGFR1 and 2 getting inhibited at the same time and at the same level when you're inhibiting FGFR3 in the active growth plates. TYRA-300 has this opportunity to fully inhibit FGFR3, not necessarily full 90-95%, but the way that you want to restore the tone to potentially normalize growth, and to do so with a nice separation from FGFR1 and 2 and potentially a nice therapeutic index to explore the right dose for these kids. That's what we're excited about taking TYRA-300, you know, into a phase II next year, we're gonna have this ability to look at multiple doses to really optimize the outcomes. That's very exciting. Just want to dive a little bit deep into your dose selection. You mentioned it's probably different from, you know, oncology applications, and you have phase I oncology trials. How are you using all the information that you will be able to get to sort of guide your phase II dose for the achondroplasia trial? Yeah. You know, we do a ton of work preclinically to look at this. We're getting as much information as we can. I think the story that's emerging is pretty clear. You can start with the data from BridgeBio, where they showed, you know, they're about one-seventh of the oncology dose, where they're starting to see some good responses in 10 kids. It's small numbers, but really, that's still a pretty big gap between kind of full inhibition, or at least the oncology dose. It highlights that. You know, we're likely not gonna dose up to an oncology dose with TYRA-300. You don't need to. The right area to be exploring in dose is gonna be somewhere, you know, somewhere below. You know, we think, you know, no more than half the oncology dose likely. When you think about this window from one-seventh, you know, up, you know, there's going to be a level there that I think is appropriate, and it's gonna be lower than the oncology dose. That makes sense. Just to kind of follow up on that, your phase II study you plan to start next year. What needs to happen between now and next year for that to kind of kick off? Yeah. Pretty straightforward set of exercises we're undertaking. We need to finish our kid-friendly formulation. There's some important regulatory requirements, and we need to talk to the FDA about those. Some of the more standard guidance they've given, making sure that we do a juvenile toxicology study and then making sure that we have the chronic dosing out beyond the 13-week studies that we've done, so that's 6 and 9 month. Those are things that we need to have ready and in line for chronic dosing in kids. We're working very thoughtfully and aggressively towards ensuring that we have all those complete as well as obviously preparing to talk to the FDA and make sure that we have all the right guidance from them to make a good study. You mentioned about kids-friendly formulation. Could you maybe add a little bit color about, you know, what needs to be done sort of to have that, you know, kids-friendly nature there? Yeah. You know, obviously you go from capsules, you know, looking at tablets, and then there's really unique forms from there where you can look at sprinkling and, you know, dissolving or otherwise. We're doing all the work to make sure that we've got a great formulation that's ready. Awesome. You know, no major barriers. It's really, you know, just doing the work and choosing the right format and moving forward. Awesome. Beyond TYRA-300, Tyra does have other assets in the pipeline. Yes. Just high level-wise, you know, what else you feel excited? Well, I, you know, I would be remiss not to mention how excited we are about TYRA-300 for oncology, not just because of, you know, where we think this phase Ib will go, which is in late line patients, but because of the opportunities in Non-muscle invasive bladder cancer. You know, the folks at Janssen, developing erdafitinib have put up some really exciting data, and I, again, commend them and the patients, highlighting what FGFR3 inhibition can do. Aside from the late line metastatic kind of 40% response rate that you see with erdafitinib, you know, an interim data showed 68% response rate in first line in combination with PD-1. That's in line with what's seen with EV. In the NMIBC BCG resistant, erdafitinib showed a 100% complete response rate, 9 patients. In intermediate risk, a 75% complete response rate. The challenge with every single one of those studies is that the toxicities are pretty consistent, and they're the pan FGFR toxicities that we worry about with the nails and the stomatitis and patients just having a hard time staying on drugs. Most instances here, you know, patients are staying on for a few months and then, and coming off. Being able to really hit FGFR3 more selectively and, you know, see the same types of outcomes in terms of initial responses but then allow those to be durable because patients could stay on drug and tolerate it is really the goal. I think we'll know a lot from the phase Ib, about, you know, what the potential is here along those lines. That'll allow us to kind of move in similar directions with phase IIs across all of those opportunities to then prove out really not just the efficacy but then that potential durability with safety. That's really exciting on the oncology side. TYRA-200 is, you know, uniquely positioned in intrahepatic cholangiocarcinoma to come, you know, behind all of the approved and end stage, or in development assets by addressing the molecular brake and gatekeeper mutations. That's what's shown up at month 10 in these patients, and they don't have great options. That's where we're focused with the study in patients that have those mutations and with prior FGFR. We'll have some additional pipeline activities. I think we're excited to talk about them, and we'll save that for a future event. Awesome. Awesome. That's exciting. Thank you, Todd, and it was great talking to you. Looking forward to the data in the near future. Yeah. Appreciate it. Thank you very much. Thank you.