First day of B of A's 2025 Healthcare Conference. My name is Jason Zamanski. I'm one of the SMID-CAP analysts here at the bank. For this slot, I'm very pleased to have join us on stage here: Todd Harris, CEO, and Doug Warner, Chief Medical Officer of Tyra Biosciences. Gentlemen, thank you. Thanks for having us. Thank you. Perfect. Maybe just to start broadly for investors who may not be as familiar with the story, you know, would you briefly describe Tyra's platform? I guess when you think, what differentiates the elements of the platform from other developers focused on FGFR inhibitors? Thanks again for having us. Tyra, we are a company focused on small molecule precision medicines and in the FGFR family, largely with our lead molecule that's an FGFR3 selective. We do all of our chemistry in-house. We use what we call our SNAP Chemistry Design Platform. It's a structure-based drug design platform that's highly iterative. Really, what's unique about that platform and capability is it allows us to solve very hard engineering problems like we did with making an FGFR3 selective molecule. Those FGFR inhibitors that have advanced into the clinic and even been commercialized are all pan-FGFR inhibitors. They hit FGFR1, 2, and 3 close family members very similarly. They do that because the active sites of those three family members are identical in that first shell. There's very little chemistry that you can take advantage of in terms of different amino acids. We leveraged our structure-based drug design approach to understand very fine differences in the active site that we ultimately exploited to make a selective FGFR3 inhibitor, which is really the first to go into the clinic and is now read out very positively in the clinic in our phase one MEC study and highlighted really the capability of the platform, making something as selective as we did. Got it. I think that's a great segue into the first question here in NMIBC. You know, when you think about the space, I mean, ADCs have proven fairly effective for treating it, but what are some of the unmet needs? You know, are there distinct populations where you think an oral FGFR3 inhibitor would be especially attractive? Yeah, let me hand that over to Doug. Sure, thanks, Todd. In NMIBC, there are different risk categories. In low-grade, intermediate risk NMIBC, that's about 70%-80% of cases having FGFR3 alterations. While ADCs have shown success in the metastatic setting, in the earlier settings like NMIBC, the focus has really been on TURBT surgery and chemo, and there are very high recurrence rates in those settings. For instance, at one year with standard of therapy of surgery, TURBT, and chemo, recurrence rates are about 30%. At two years, they're about 40%. While there are a lot of different drugs in development, all of those drugs are procedure-based and involve intravesical administration of agents where TYRA-300 is an oral therapy, so it really solves a need there. Got it. You know, when you think about duration of therapy classically in NMIBC, it's historically been longer than other indications. I guess, you know, how sensitive do you think regulators are to side effects? I guess what gives you confidence about moving forward with 300? Yeah, so I think there certainly is an emphasis on safety and tolerability in that setting. First of all, because these patients are generally very healthy. Secondly, as you mentioned, there is long duration of treatment. Based on our work in MUC in the metastatic setting, where we tested much higher doses but evaluated lower doses, we feel the doses we are evaluating at 50 and 60 milligrams q.d. will be very well tolerated in this population. We do not foresee an issue there. Great. About how quickly do you think you'll be able to generate top-line results? Are there any signals that you think would be especially de-risking this early phase? Maybe I can take the latter part first. Complete response at three months would be an early signal of activity. That would give us a real understanding, early understanding of efficacy that will help us de-risk going forward. I'll hand it over to Todd to talk. Yeah, in terms of timelines, we're excited that, you know, we're activating our first sites this quarter. We're anticipating our first patient dose this quarter. We're really looking to fill these two cohorts of 50 and 60 milligrams as we get throughout the year, which should get us, you know, we haven't committed to a specific timeline, but as we get into early next year, an opportunity for that initial three-month CR rate to be discussed. Obviously, we'll want to follow those patients for longer, but that CR rate really is, I think, the critical top-line data. We're talking about a dose that can essentially chemo-ablate the tumor, which would very much likely be a dose, if maintained, would keep those tumors at bay for very prolonged periods of time. Got it. Okay. Switching gears somewhat, you're also evaluating 300 in achondroplasia with phase two BH301 underway. I guess similar question as before, the CNP class has demonstrated solid efficacy, but where do they fall short? Yeah, it's a really exciting space, and it's really exciting to have options for kids. You've got Voxzogo that has an accelerated approval. It's on the market. It's generating, you know, what would be about a 1.57 cm incremental benefit each year for these kids. Their phase two, phase three data, you know, read out approaching an annualized height velocity of about 6 cm total versus what would be expected in the natural history of about 4 cm. Where that falls short is kids without achondroplasia are going to be growing about 7.6 cm per year from age one plus. And BioMarin just had some data over the weekend where they highlighted that if you were to treat a child from six months and inject them every single day with Voxzogo up through those growth plates, they could expect optimistically that that kid might be able to grow 26 cm. The gap is more like 46 centimeters between typical height adult male and a male with achondroplasia. You're about addressing half of the final adult height benefit. All of these things are important as surrogates for the key clinical sequelae, which are spinal stenosis, foramen magnum stenosis, reach gait, and some of the pain and surgeries associated with the condition. Being able to truly modify the target, which is FGFR3, such that you're able to move the FGFR3 activity to something that's more physiologic could really close that gap. Even, you know, Ascendis, they're generating very similar data with CNP. There's really no more dose response curve with CNP. You can give more. It doesn't change that annualized height velocity above 6 centimeters. That's different with FGFR3 inhibition. Now, we've proven the concept thanks to the great work that BridgeBio did with infigratinib in a phase two. They also were able to get to about 6 centimeters AHV, but they're just beginning on the dose response curve. They're using a dose that's very low. It's one-sixth of a dose that you would use in an oncology setting trying to engage the target with an IC90. That gap of sort of one-sixth of lower dose highlights just how minimal their target engagement is. Kids that do go on full oncology doses, drugs like erdafitinib or Debiopharm had a drug as well, and they would do this because of brain tumors, when they have open growth plates during that period of time, you see massive acceleration of growth, on average about 19 centimeters per year. That highlights the dose response curve we're talking about, which is a very, very wide dynamic range. Now, you wouldn't want to intentionally target that IC90 inhibition of FGFR3 with any of these kids because that level of and speed of growth can lead to overgrowth challenges, something called skiffy or fractures that would be problematic. However, we can do better than these existing therapies. You know, growth hormone, for example, in the first year typically takes kids to about 8.5 centimeters per year very safely in achondroplasia. Voxzogo, when used in conditions where FGFR3 is not overexpressed, so FGFR3 wild type, that break is not in, they're able to move kids with short stature from 4 centimeters a year to 8.5 cm per year very safely. That's really where we're focusing. We want to get to that eight, eight and a half centimeter per year. It will double the efficacy of what everyone else has seen in this indication. There is really strong evidence that that can be done safely. We know we just need to hit the dose response curve. With the data we have already read out in the fall, we know we have the therapeutic index all the way up to half the oncology dose, which is as high as we would want to go to avoid overgrowth. We do not see any hyperphosphatemia. We do not have any ALT or AST increases. We do not really have any AEs of significant concern. We're going to be able to engage the target beyond where infigratinib was able to go with their very low dose and ideally hit that annualized height velocity surrogate and ultimately make a much more meaningful impact on the clinical sequelae that are as most important. Got it. Maybe let's switch gears again. Obviously, as you mentioned earlier, we saw the SURF301 data last fall. You know, as you think about 300 and how that's differentiated from both J&J's erdafitinib, but also Lilly's Loxo, you know, when you think of that constellation there, where does 300 fit in? So, you know, first of all, because it's selective for FGFR3, we see clear differentiation when it comes to side effect profile against erdafitinib. So erdafitinib, you hear providers say it's as bad as chemotherapy because it really is. You have nail toxicity such as nail loss, nail infection at over 70%. It's single digits with TYRA-300. You have stomatitis or mouth ulcers over 55%, single digits with TYRA-300. So there's a real difference there, as well as efficacy where we saw a 55% response rate versus 35% with erdafitinib. With Loxo, it's BID dosing. And what we saw there is they haven't chosen a dose. They presented data looking at three different doses, but you have very high rates of diarrhea at around 76% and high rates of hyperphosphatemia at around 36%. So we see real differentiation there both on efficacy as well as safety. Are you winning on efficacy because your patients are able to stay on longer, i.e., the safety profile? Or are you winning on efficacy because you're winning on efficacy? Right. So it's likely a combination. You know, it's still early days, but certainly being able to stay on a highly active drug longer is going to result in more efficacy. Erda, its efficacy is pretty limited. Not only does it have a 36% response, 35% response rate, but the duration of response is actually less than five months. Some of that's due to non-selectivity. With efficacy, other of that is due to non-selectivity resulting in toxicity. Got it. As we think about the updates as we move forward here, what are the benchmarks for success? Yeah, so our focus, you know, really prioritization is reflected in the phase twos that we're opening. NMIBC, ACH, these are our big and exciting opportunities, very large markets. For NMIBC, the benchmark, I think, has been really well set on efficacy when we look at both Part 210, the locally delivered erdafitinib, and then erdafitinib given orally at a low dose of 6 milligrams. In that oral systemic exposure, they got an 83% CR rate. That's, you know, an excellent efficacy signal. However, it came with all of the toxicities. As we've tested the profile with KOLs, they have highlighted, especially for an oral, that even a 70% CR rate would be very attractive as long as you're choosing a dose that's really well tolerated. Part of our strategy here is evaluating multiple doses, trying to find really the most tolerable dose that can hit that 70% CR rate because we think that will get the most use and, you know, have the most long-term benefit for chronic dosing with patients. I think I already talked about the achondroplasia benchmark. Here, we're looking to exceed that 6 centimeter, get to 8, 8.5 centimeters AHV in terms of our initial readout from higher doses in that phase two. Got it. In the brief time we have left, obviously you're well capitalized. I think it's at least through 2027. You've got three phase twos underway, three different conditions. Then on top of that, you've got 200 in ICC and 430 in HCC. What are the puts and takes here in terms of prioritizing programs? Yeah, we've been really focused on making sure that we manage our cash effectively. We're in a great position with, you know, $318 million as of our last quarterly release. As you mentioned, being able to have money through 2027. A big part of that too is managing where do we want to prioritize that cash. We'll be able to get the key phase two readouts in NMIBC and in achondroplasia. Those are our top priorities. We'll be able to get our dose escalation and some initial dose expansion with TYRA-200 and TYRA-430. One of the things we're being intentional about in the metastatic urothelial setting is that we don't want to necessarily at risk rush into a phase three, which is going to be a very expensive spend while we're waiting to get this very meaningful phase two data out from these other indications. We're actually pulling back a little bit, not opening additional sites there, whereas we are opening a ton of sites for ACH and NMIBC. That's a very intentional exercise so that we've got the levers to make sure we can manage our cash through getting all of the data that we need to see. Perfect. Exciting story. Todd, Doug, thank you so much for joining us. Thank you. Appreciate it.