Okay, why don't we go ahead and get started. Thanks, everybody, for being here. My name is Chris Raymond. I'm one of the senior biotech analysts at Piper Sandler. It's my pleasure to introduce our next presenting company, which is Tyra Biosciences. We have with us Todd Harris, the CEO. We have a ton of questions and stuff to dive into. Before we do that, just some housekeeping. This is a fireside chat format, so it's meant to be informal and participative. So if you have any questions or anything you want to cover, just raise your hand. I'll make sure your question gets asked and answered. So really interesting company, lots of stuff to get into. But maybe for folks who might not be initiated into the story, Todd, if you wouldn't mind, maybe just level set for us the Tyra setup and elevator pitch, if you will. And then we'll dive into Q&A. Sounds great. Thank you, Chris. Thanks for having us here. So Todd Harris, Tyra Biosciences. We're a company focused on small molecular precision medicines. We make our drugs from scratch. Come visit us in Carlsbad, California, and you can see the process. Our focus as a company really started in the FGFR family with an initial goal of making an FGFR3 selective inhibitor driven by a really, really big unmet need in bladder cancer and a really compelling unmet need and large opportunity in skeletal dysplasias, including achondroplasia. And to date, the way the field has prosecuted targets in the FGFR family has made these pan-FGFR inhibitors. That means they hit FGFR1, FGFR2, FGFR3, sometimes FGFR4 all the same. FGFR is a family that's important in a lot of biology. So what happens is when you hit everything together, you get a lot of side effects as a result. And by sparing FGFR1, FGFR2, and FGFR4 and just hitting FGFR3, our goal was really getting to a superior safety profile that could translate to more meaningful efficacy. I'm really proud and excited about the data we just disclosed earlier this fall that proved just that: very compelling efficacy, better than anyone else has seen with the pan-FGFR inhibitors in a metastatic late-line urothelial cancer population, and incredible improvement on the safety vis-à-vis sparing the FGFR1 and FGFR2 toxicities. We also have a couple of other molecules, FGFR2-focused TYRA-200, and then a hepatocellular carcinoma FGF19-driven targeted drug that inhibits FGFR3 and FGFR4 that's going to be going to the clinic as well. So I want to dive into the 300 and the program. But maybe just real quick first, there's a lot of targeted oncology development companies that talk about having a differentiated platform. Some generate molecules that actually have impressive clinical data, and some don't. You guys obviously have done this. Talk about the SNAP platform. And it is impressive to your point, you've developed these assets from scratch. Just give us a sense of what differentiates that platform from others. Yeah. Making a molecule from scratch is a near impossible task. You have to plug 1,000 holes in terms of the checkmarks of what goes into a good molecule. The initial and very hard thing for the industry has been, how do you make an FGFR3 selective over the other isoforms? Because the active sites are identical. So structure-based drug design is the fundamental approach of our SNAP chemistry platform. But built further into that is a rapid and iterative approach to structure where we'll do in-house hundreds of co-crystal structures on the same protein and different proteins or related proteins and multiple molecules. And we do it in a couple-day turnaround. And that allows us to get information back to our chemists to iterate the drug design process much faster than you can conventionally do, especially if you're outsourcing crystallography. We also in-house have all of our cell-based assays that we've built out and engineered, as well as an in vivo team, all of whom are sort of tuned for a very rapid iterative turnaround, and when you're trying to design an FGFR3 selective, again, you can't rely on an amino acid shift to build chemistry around. You actually have to look at very subtle differences in the way that the protein is moving or changing with our chemistry evolution, so being able to do that rapid turnaround, I think, differentiated us over others in getting to this target product profile before anyone else could. So maybe for folks who are not initiated to the story or understand maybe the FGFR sort of market, there are a few options available now. Talk a little bit about the current state of the field and what the unmet need is here. And specifically, you mentioned these pan-FGFR inhibitors do have safety and toxicity issues. Maybe dig a little bit deeper into exactly what those are and what you solve for here with 300. Yeah, and I think it's important to highlight that this is a story about efficacy, first and foremost, driven by the ability to improve safety. And I think that's what was demonstrated initially in our data set this fall. The landscape really looks like this. In bladder cancer, you have one approved agent that's a pan-FGFR inhibitor, and that's J&J's erdafitinib. It's in a late-line bladder cancer setting. It generated a 35% overall response rate in their confirmatory study, and it comes with debilitating toxicity so that 70% of patients that go on the drug are going to dose-reduce. The primary driver of that is first nail toxicity, so this is nails peeling off due to FGFR2 activity, followed by stomatitis as their mouth sores that keep you from being able to eat. That happens in one in five patients, followed by PPE, this soreness in the hands and feet. Then you have this really elevated amount of hyperphosphatemia. So you don't see it getting significant uptick. But it was also hampered in another very meaningful way. J&J initially looked at using this drug as an oral therapy for intermediate risk and high-risk non-muscle invasive bladder cancer. This is a market that they've definitively called a $5 billion market. And that THOR-2 study read out positively 83% CR rate in the intermediate risk NMIBC setting at a lower dose. But the toxicity was too problematic. And so now they've adapted that for an intravesical delivery that they still believe is a great opportunity. And I think it'll be a great option for patients. But really, the Holy Grail is a well-tolerated systemic oral therapy that reduces the recurrence in this intermediate risk setting. And that's exactly, now with the data we have in hand, the translation to where we're going to go next. So we've disclosed that we'll be submitting the IND before the end of the year for an intermediate risk NMIBC study. This initial readout for confirming efficacy is really a three-month CR rate, where erdafitinib saw an 83% CR rate. We're targeting seven out of 10 patients are better here as being a really meaningful bar of efficacy as we've talked to urologists. But then continuing to show that really clean differentiation on the tolerability profile, where erdafitinib absolutely fell short. That's going to be a game-changing target product profile in this setting. And we can talk more really around the details of why and how. And then finally, we've talked about bladder cancer, but there's a whole entire other space of FGFR3-driven skeletal dysplasias, including achondroplasia or dwarfism. This is an alteration in one amino acid of the FGFR3 gene that causes overexpression. This is a gene we can target, and we can target safely. Their BridgeBio has pursued using a pan-FGFR inhibitor in this space. Again, this is a story about how do you get better efficacy because the pan-FGFR inhibitors need to go with an exceptionally low dose to avoid any toxicity tolerability issues in these kids and are leaving potential efficacy on the table. For the same reason, we now actually are advancing the same molecule. We now have an IND cleared, and we'll be dosing our first patient early next year. That is a whole nother opportunity to show that we can differentiate on efficacy with this highly selective molecule. All right. Great. So let's maybe ask a few more sort of detailed questions on the data you had at the Triple Meeting. So just maybe first and foremost, in the study, I think you started at a pretty low dose. And the two highest doses were really in your target coverage area. Maybe talk about why you started so low. I know you mentioned the preclinical experience. But why did you start so low? Understanding that preclinical experience with animals that can't tolerate it, but there is a decent amount of patient experience with this mechanism. So given the backdrop of that, why did FDA sort of ask you to start so low? Yeah. This is a very standard oncology procedure where your preclinical model predicts your starting dose. And I think there's an unusual effect in the preclinical models where rodents have growth plates that are open through life. And other large animal species you typically start treating like dogs when the growth plates are still open. That means that the FGFR3 effects on the growth plate can actually drive toxicity. And that toxicity is overgrowth. You push the growth function so hard that the bones grow really fast during the period they're on drug, and then you can see some fractures. So that's going to occur when you start to inhibit at an IC90 the FGFR3 target in any mammalian species that has open growth plates. So that was just a simple driver. With the toxicity seen from overgrowth, you need to start at 1/6 of that dose. So we sort of by definition from FDA's requirements were 1/6 of what we anticipated being the IC90 target we wanted to hit. As a result, we just did single patient dose cohorts for our first dose, for our second dose, and then we started to expand around where we would anticipate we're getting into better coverage. Keeping in mind, to your point, the real hook here is the safety differentiation versus erdafitinib. I think one of the things that maybe caught the attention from some investors was this AST/ALT elevation signal. You had one discontinuation from a grade three ALT elevation. I think anybody who follows this space understands you see a signal like this with a lot of TKIs. Maybe just contextualize this signal in the broad scheme of treating with this modality. Yeah. So I mean, first off, many patients come on study with elevated LFTs. That's because many of the patients have liver met. We certainly saw that. Many patients come either with elevated LFTs or at risk because 90% of the patients that came on study were on a PD-1 inhibitor that does this. And if you just look across solid tumor TKIs that have been approved with a similar level that we saw of elevated LFTs, you have infigratinib, erdafitinib, pemigatinib, futibatinib, all the pan-FGFR inhibitors with the same amount. You also have afatinib, osimertinib, the $6 billion AstraZeneca drug. You've got selpercatinib, pralzetinib. Really, across the board, TKIs, this is just something you typically see at the levels that we're seeing. What's particularly encouraging about what we see here and that we highlighted because we did treat a lot of patients at doses below our 90-mg dose that was most effective at the 60-mg dose, which is most relevant for our intermediate risk NMIBC setting. Out of the 10 patients that started at that dose and the 4 patients that escalated to that dose, so 14 total, we had one grade 1 ALT increase, no impact on AST. That's on par with what you might see with a statin, and that's really what urologists have said is we want to see sort of a statin-like TPP here for exceptional tolerability, and that's essentially the starting dose we're going to look at and dose around for our intermediate risk NMIBC setting. We saw nothing at 40 mg and below. And the 10, 20, 30, 40-mg adult doses are what correspond to the doses we'll be treating with achondroplasia. Those are doses that are hitting FGFR3 and engaging it more than can be engaged with a pan-FGFR inhibitor in children because of the very clean profile we see with no hyperphosphatemia. We saw no dose reductions. We saw no ALT/AST increases up through 40. So we're really excited about actually the tolerability profile that we see with this drug across each of the relevant doses and the phase 2 dose exploration we're going to be doing. Let's jump into achondroplasia then. I think that's the opportunity that is getting more and more attention. You've obviously got Voxzogo out there doing very well commercially. Ascendis has their CNP analog as well. And then you've got BridgeBio with a similar mechanism to what you guys are pursuing. All of them so far have been relatively in the same sort of range in terms of AHV, annualized height velocity change. Not to ask you to sort of set the bar here too high, but what's missing from those therapies today and how you feel 300 can actually change the game? Yeah. So all of those therapies, when you look at the annualized height velocity achieved at 12 months, infigratinib just published in the New England Journal, 6 cm AHV. Ascendis just read out a phase three at 5.9 cm. And BioMarin saw in their phase two at 5.9 cm. So that's in the backdrop of a natural history where these kids will grow on average four cm. But children that don't have achondroplasia are going to be growing 7.6 cm on average. So you're sort of halfway where you want to be with these drugs. And we know with CNP that you've lost a dose response curve. You can give more CNP, and you don't exceed the 5.9 cm. What we don't know with FGFR3, well, we sort of do, but we didn't have the data from infigratinib is they stopped dose escalating once they were engaging FGFR3 at kind of an IC10, IC20. That was their 0.25 mg per kg dose. It's 1/6 of their oncology dose, and the reason they stopped, they highlight very clearly in the protocol that was published in the New England Journal of Medicine is that at any higher dose, they see hyperphosphatemia, which is a risk factor because it can lead to tissue calcification and a number of issues. And that is a function of when your IC50 curve for FGFR1 and three overlap entirely, you can't push the FGFR3 engagement to an IC50 without pushing the FGFR1 engagement to an IC50. So you're going to run into hyperphosphatemia. So they're capped due to safety and aren't able to generate the efficacy you would want. That's what an FGFR3 selective can achieve. We can now, and we've demonstrated with the data set we just read out, we can move up to IC50 coverage without hyperphosphatemia, without liver enzyme changes, without AE profile that is of any concern to us from what we've seen so far. So that gives us this window of FGFR3 engagement that can't be achieved that we're now clear to proceed to do that. So it sets us up for a really exciting path forward. And it only can be done if you have chemistry that is FGFR3-selective. Understanding the objective here is to have this sort of 7-8 centimeter sort of absolute number. Again, clinical trial experience doesn't always go as planned, right? There's an opportunity that you could miss that. Talk about the differentiation, especially if you've got a post-approved infigratinib world, right? You've clearly got a differentiated profile there. And you'll have other therapies. Say that just talk about the differentiation on the safety front that could also provide some utility. Yeah. I mean, let me highlight. I think from what I've read with where BridgeBio is developing, I think they're developing a very safe drug. They're choosing a very low dose that hopefully allows that, and hopefully it's a great option for kids. So I think safety in this indication is key. And efficacy is really what's missing. Being able to achieve efficacy while still maintaining that safety is where TYRA-300 really differentiates. And the evidence of potential efficacy improvements is very clear. There are these case studies published of kids that go on full oncology doses of either erdafitinib or other pan-FGFR inhibitors. And what you can see during the period of time they're on those drugs is that their annualized height velocities move from seven or eight centimeters a year up to about 20 centimeters per year. And occasionally, they will see some fractures and some bone effects just like we talk about in the non-clinical setting. So when you really push towards full IC90 engagement, yes, you accelerate growth, but then you can start to see problematics from growing too fast. But that dynamic range is really large. And we know that the current agents aren't even hitting physiologic growth. So it really clears the path for us that this is just a dosing situation of bringing FGFR3 tone back into the right line. And we think we'll get an exceptional efficacy while maintaining the safety due to the selectivity. So still becomes a game of efficacy while preserving safety. But we think the data are there to show that the efficacy can be pushed in the right way. So on that track, maybe one more question on achondroplasia. We've seen now BioMarin and BridgeBio both expressing hope, right, that they could have an impact on proportionality. And that's another major sort of concern in the field is that not only do you have a growth benefit, but you can have an impact on proportionality, which is probably hard to measure in a 12-month study, but is a meaningful long-term. Just talk about. I asked you this last night. I think it's intriguing to think if you can have an outsized effect on growth that perhaps there's a benefit then on proportionality. Just in terms of what your KOLs or investigators are saying, maybe handicap your view of how that can sort of impact proportionality. Yeah. I think it's important to highlight proportionality. It's very important, but it's still a surrogate of the clinical unmet need. Things like improving gait and reach, spinal stenosis, surgeries, and some of the complications that individuals with achondroplasia face are what's really important, and annualized height velocity is a surrogate. I think proportionality is a surrogate that gets you even closer to your belief you can make an impact there, and I think this is just a matter of really engaging the target the right way and giving sufficient time to see the benefit play out, so you can only expect so much in one year, but if you're pushing the target harder and in the right way, I think the increased likelihood you can see that in relatively shorter periods of time, so we're certainly optimistic. That's why we're moving forward, and we're actually doing all the work to look at those exploratory benchmarks, reach, gait, and find issues that we think really are going to matter most to the population. Okay, so one more question on achondroplasia. Sorry. Just on the setup and the next sort of catalyst, you're filing your IND pretty soon here. And it's, as you've explained, a 12-patient study with four different cohorts. And so the objective here is to have, I think you said, first to have safety data. Obviously, that's important. But as I understood, the really first efficacy sort of cut will be at six months. I know you're not right now in the business of providing guidance on catalysts for 2025, but just talk about the timing of enrolling that study and when you think we could have how the data sort of plays out from those 12 patients. Yeah. IND is already cleared. So we're in the process of initiating our first site, and our first patient planned dosing in Q1. We're in the process of expanding our regulatory authority approvals to proceed in other countries that will be meaningful. And the initial data set that you can expect to see here is a 12-patient sentinel safety cohort split where three patients treated at each of the four doses. There is a DLT window as we escalate between each of them. It's a 30-day window. What's meaningful is that that's data, particularly starting in the first half of the year that we'll start to see is are each of these doses safe during this DLT window for these kids and well tolerated. we have a 30-day window between each of these dose escalations, so you're really sort of four months from first patient to the soonest you can have all these doses cleared, and then six months to AHV across all of the patients from there, so these data will read through pretty quickly. This will allow us to look at a dose response analysis in AHV. That's what we'll see with the target of exceeding the 7 centimeters per year six-month AHV that others have seen, and that's, I think, the first meaningful sign of efficacy that we're starting to achieve the target that we want, and it'll come relatively quickly with this first 12 patients, but we'll be filling in cohorts one and two, additional patients at the key doses to just build out that efficacy for future readouts as well. And then, same question, I guess, on NMIBC in terms of the cadence for the data for next year? Yeah. So I think surprisingly, just because of the endpoints, we've committed to an IND submission before the end of the year that would get us into a study next year with a three-month CR rate as being the initial data readout that combined with safety. So that actually gets us pretty quickly into data in NMIBC potentially before other indications. And then, of course, we've got the metastatic we continue to enroll in. So you've got three phase 2s, staggered data points on safety and efficacy coming out beginning next year and then moving very meaningfully beyond that as we proceed. All right. Lots to look forward to. Thank you. We're out of time. Thank you very much.