Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for attending TD Cowen's seventh annual Oncology Innovation Summit. For our next session, very excited to have a fireside with Tyra Biosciences, and it's my pleasure to introduce Todd Harris, the CEO. Todd, it's a privilege to have you here. Thank you very much for joining me. Thanks for having me, Tyler. It's great to be here. Of course. For those of you in the audience, if you have questions, you can go ahead and submit them via the portal, and I'll do my best to get them answered by the end of our discussion. As you all may know, Extel voting kicks off today, and the TD Cowen Biotech team would appreciate your support if you feel that we have earned it. With that, we'll go ahead and get into questions, starting with NMIBC, which has become a therapeutic area of focus more broadly across multiple programs, but in particular for Tyra, especially in the last six to 12 months. Let's see. Starting with IR NMIBC, Todd, maybe you could just start by describing why you decided to update the phase II SURF302 data in August as opposed to June or by the end of Q2, and how many patients we can expect from that update? Yep, Tyler, we're happy to do so. Now that we've gotten through Q1 enrollment, we have a pretty solid line of sight to when we'll have three-month data in the first set of patients. That target's been 20+. We'll be able to hit that now with data that we can release in August. A lot of our enrollment came in in Q1, and it was ramping up through an inflection point there. We had about two or three sites available last year, and then 20 sites came online at the end of the year, and now we're at nearly 40 sites. We're at a good rapid clip month-over-month. The update and the timing was just to ensure that we could have enough time for patients to do their follow-up three-month, have that 20, which would be about 10 or more in each dose cohort for efficacy. We do expect a bigger safety data set because patients are continuing to enroll above and beyond those that are already in, which we're anticipating. We also just operationally, there are times where you want to do a confirmatory biopsy, which could add a couple of weeks past the cysto. Just to add ample time, we decided August would be the right time to have that data set. This is a data set that's very important to us because it's just this initial proof of concept. It's either a data set that's sufficient for us to kick off the phase III planning, select a dose, talk to the FDA about what would be a potential adjuvant design. If the data weren't exactly what we anticipated, we do have the opportunity to do a dose up or a dose down. At this stage, we feel good about the dose selection. We're looking to fulfill the remaining patients. We're looking for efficacy as well as monitor safety. Our target is a 70% CR rate or better, as well as a safety data set that's consistent with the 22 patients that we treated at 40 or 60 milligrams at MUC, which is published on our deck. Hitting that, I think, is going to be home run data. The really interesting thing about the oral approach is you're putting daily pressure on the tumor, and just the pure convenience factor for the patient is a game changer. Hitting 70% CR rate or better, we think is going to give us that really best-in-class TPP with this approach. Understood. The 70%, can you just elaborate a little bit more on how you selected that? Is it kind of based upon the thinking that even if you have a CR rate that's maybe 10% or 20% lower than intravesical approaches, such as UroGen's ZUSDURI, that patients would still opt for an oral administration? Yeah, it really is that. It's important to remember that today, for standard of care, patients could receive six separate treatments of intravesical chemo after TURBT. There's likely evidence to suggest that's going to meaningfully improve the efficacy, but it's simply not done from a convenience and a patient burden perspective in that community setting. That's a real tell. This idea of coming into the office every single week after week, to have multiple catheterizations and have chemo or virus or other things pushed into your bladder. It's not convenient, and many patients are just deciding to just wait for their next TURBT, for example. An oral therapy really changes the game because it avoids that urethral violation that's kind of week after week or quarter after quarter or even daily in the case of having a device placed into your bladder. Great. As we think about comparing the CR rate, some have asked about the marker lesion design and comparing it relative to kind of chemoablative approaches like UroGen, where, I guess, in the trial, small residual lesions are left, as opposed to a patient that might have a higher burden or a more diffuse disease. Curious to get your thoughts on that as well. We are not intentionally with this study designing a chemoablative approach. We are taking the same approach that J&J took with. They tried it with THOR-2, but then ultimately took it with TAR-210. Even a small marked lesion is evidence that you've got the right level of target engagement to be successful in an adjuvant study, which is really the main approach that sponsors are now taking. We are not looking to have an entire field of tumor disappear, like you might be doing in the ZUSDURI trial. Really, the benchmark should be, what did the THOR-2 data look like at three months? What did the TAR-210 data look like at three months? Here you're actually talking about those data sets being 70%-80%. Interestingly, both THOR-2 and the TAR-210 phase II matured to improve the CR rate. As you got to six months, you actually saw the CR rate goes up. That, again, highlights the benefit of constant treatment of FGFR3 in suppressing the tumor is you're not sort of doing this chemoannihilation up front and then hoping it doesn't come back. You're actually shrinking the tumor, and then that persists for a very long time, and you see that in the durability. Seeing something similar to what was seen in THOR-2 at three months, the TAR-210 example, would be a huge success. The way we see that's basically greater than 70% CR. Lots of meaningful evidence that the tumors are shrinking across the patient population. That data will mature well, we think. Okay. As you think about expectations for the CR rate at later time points or durability in general, with TYRA-300, how are you setting your expectations there? I mean, we've got the THOR-2 data. Two important highlights there. For any patient that stayed on drug that had achieved a CR, they maintained that CR at 12 months, 100% durability. There's also some interesting data embedded there as well. They did have a few patients that initially showed up as PRs. For any patient that stayed on drug that initially was a PR, they converted to CR. Just great demonstration. Some of that did happen later at six months. Just a great demonstration that if your initial data set is showing that tumors are shrinking and you're getting a high rate of CRs, that the durability expectations can be quite high. Understood. With the update in August, are there going to be any efficacy endpoints beyond the three-month CR rate that are shared that we should focus on? Again, the comparison to THOR-2 would be responders. You could be a responder without a CR. There was 17 out of 18 PRs or responders, either PR or CR. That's obviously a pretty exceptional outcome to think about 95% of patients benefiting. We're looking to hit similar target engagement, get a majority of patients getting to CRs and a great outcome. That's going to be evidence that we're hitting the target. Obviously, what's most important is coupling that with safety and tolerability, and that was what obviously made erdafitinib THOR-2 data not move forward, was just patients weren't really tolerating the drug very well. A well-tolerated profile with efficacy is really going to be an exceptional data set that we're looking to achieve. Yeah. Perfect segue. On the safety front, is there a specific threshold of Grade 3+ AEs or Grade 3+ AE rates that you think would be acceptable once the safety's reported? Yeah. We're looking at very low rates, of course, so looking at single-digit Grade 3 events. Again, this is an elderly population, so if you look across treatment emergent events in other studies that were done in this, like look at the XTANDI studies, there can be some low rates of Grade 3 events even on a placebo. Understanding that. Similarly, we like to compare sort of when people think about diarrhea, there's some XTANDI studies where the placebo had 20% low-grade diarrhea, which is consistent with our expectations here. Having a very low rate of any potential Grade 3 events is going to be important. Largely Grade 1 or 2 events. For us, we just want to hit something that would be similar to what we've already generated in 22 patients that we treated at 40 and 60 in the MUC study. Beyond diarrhea, are there any specific AEs of interest that you guys will be focusing on as well? The key one that showed up at 90 mg was increased AST/ALT. You saw that markedly move down for the 40 and 60 mg. We're looking to see that again. If you look at erd afitinib in the metastatic setting, had a similar 45% AST/ALT elevations that we saw. When they dropped the dose down to six mg, that came down to about 17%. That's in line with ZUSDURI and INLEXZO that both reported out what is about 15% and largely Grade 1 AST/ALT. That's a good bar. Looking to be able to come in line at or better than that at a dose would be important. Okay. That was mid-teens, all grade LFTs that you were citing? Yes. THOR-2 had that, and INLEXZO has that, ZUSDURI has that. Okay. What about the Grade 3+ LFTs, in particular? Obviously, the fewer, the better. Yep. What- Yeah. We would look for very few, of course. Okay. Very low rate of anything like that. Okay. All right. Let's assume these data are positive. You've got a reasonable sample size, as you alluded earlier in this conversation. It should allow you to potentially have discussions with regulators. I guess how quickly do you think TYRA-300 could advance into a pivotal trial in IR NMIBC, and what that might look like? Yeah, of course, it's going to be data dependent, and we would give guidance based off of that data. You could imagine a data set that would be enabling, you sort of coming in the August timeframe. The period of time at which we could get that in front of FDA after requesting a meeting, and then have a phase III sort of aligned on could put us into obviously launching a study early next year if we go through all those steps. Understood. From study start to top-line data, how long would you expect that to be? Historically, the ZUSDURI trial took quite a while. We saw CG move a lot quicker with their trial. What's your latest thinking there? Yeah. We'd like to benchmark ourselves against CG, with a similar study design and a similar aggressive scenario for patient enrollment. I think we don't anticipate nearly as many challenges in an adjuvant study for enrollment as you might in an ablative setting. Some of the challenges in the ablative setting is just the requirement for biopsies and confirmation of FGFR3 and kind of not going through standard of care and asking a patient to come in. Those can create complications. It makes it a little bit more challenging to run phase II studies like we are with that signal-seeking marked lesion. What we've been surprised by is that the interest of an oral therapy avoiding intravesical burden has certainly created enough enthusiasm for us to see good recruitment. I can imagine randomizing post TURBT in a larger phase III study should be able to enroll quickly, so as we get to the right sites and get them open. Yeah, I'm not surprised to hear about the enthusiasm for an oral therapy as opposed to the repeated catheterizations. Again, investors very focused on CR rates and eventually durability curves. Do you feel investors still fully appreciate the potential value proposition of an oral and its ability to see uptake, even in the community urology practices and what the dynamics are there? How much evolution do you think needs to happen on that front, as Davo approaches the market? Yeah, look, I think we still have quite a bit of evolution to telling our story. These things aren't always met out the gates with as much enthusiasm. I like to talk about the drug that everyone knows about, CAVERJECT, except maybe you don't know about it because you know about the drug VIAGRA. CAVERJECT was the injectable ED drug that first to market. Many folks thought, "Who would do oral systemic therapy for an ED indication?" Well, the rest is history, right? We get a well-tolerated drug here. This is a game-changing profile that patients are seeking. I think you cited it well in one of your recent analyst updates, longstanding dream, and we've heard patients say again and again, "Wouldn't it be great if we just had a targeted pill that could treat my disease?" It is really the dream, to avoid all of this urethral violation. That comes with efficacy and a well-tolerated drug, and I think we could have the potential to show early signals that we are absolutely on the track. It's really looking at that THOR-2 benchmark, looking at our safety benchmark, and coming in line there, I think would be an unbelievable outcome. Yeah, indeed. Can you talk about, I guess like enrollment, are you seeing similar enrollment in the academic settings as you are in the community? Do you think that it's an early indicator of what you might see commercially? Just curious to get your thoughts there. The key difference between academic and community when running a clinical study is that community studies can get up and running within a few months. Academic settings can typically take six-12 months. Once academic settings are up and running, our experience has been they could meaningfully contribute to enrollment. Those long delays have been quite problematic for running these kinds of studies. Got it. Okay. Last question just on the community setting is, obviously there's some sort of reimbursement for doing these procedures with intravesical therapy. How might some of these practices be able to account for that potential lost revenue with an oral therapy? Yeah, there's been a long-term strategy and development in the urologist office of helping them get licenses within their state for an in-office dispense pharmacy that can be administered through Cardinal Health's division, Uro GPO, for example. That allows physicians to essentially share in the economics and not be penalized for choosing procedure over an oral. If that physician's essentially made economically whole, then it's in their interest to provide whatever is the best treatment and most desired treatment for the patient. I think there's now a system that's been set up largely for the oral prostate cancer drugs. That really removes a disincentive to oral and encourages whatever's best practice for the patient. We'll take advantage of being able to launch right into this setting, and a great case study would be ORGOVYX, which is replacing Lupron for what's essentially medically induced castration for early prostate cancer. That transition's gone quite well. ORGOVYX has seen significant uptake as a far more preferred treatment paradigm for the patient, and launching right into this in-office dispense pharmacy model in the community setting. Very interesting. All right, let's continue under the Davo three-by-three strategy with upper tract, which could potentially be the fastest path to approval. Maybe you could just elaborate on why you decided to add this indication on fairly recently, and why you believe Davo is particularly well-suited for it. Yeah. There's a story worth telling here, which was Surena Matin at MD Anderson actually approached us. He approached us years ago, and then he approached us again after he saw our data at the triple meeting in the metastatic setting to say, "Hey, I've got some experience treating upper tract patients with pan-FGFR inhibitors. These drugs were not well-tolerated." He had tried this with infigratinib, "I would love to use your drug." That obviously caused us to take a step back to look at the market, look at FGFR3 positivity, look at his data, and it really convinced us that this is a perfect fit for a drug like dabogratinib. There's really no great solution. These patients are losing their kidneys nearly half of the time, despite this being an indolent disease that's not likely to significantly progress. All of that came together, and we worked with Surena on designing this. We were also very encouraged by the regulatory path, which was pioneered by UroGen with a 70-patient single-arm study for full approval. We put a protocol together that had a Part A for dose selection, a Part B for potential registrational intent. We talked to FDA to get this going. We've enrolled now our first patient and talked about next year being, at least for Part A, some initial data that would allow us then to quickly leapfrog into a Part B after engaging with FDA for registrational intent. We're taking all comers because FGFR3 positivity is so high, and diagnosis can be a little bit challenging sometimes. We'll be doing retrospective analysis to ensure that this is indeed all comers has real benefit, and providing that data in support of moving into Part B. Initial data next year that could potentially be registration enabling. Is that correct? Initial data next year wouldn't necessarily be a standalone registrational enabling. It would be dose selecting to move into Part B, which would be registration enabling. We'd certainly hope that all of the patients that get the right dose could be part of an ultimate package, and we're looking for this single study to potentially be sufficient for approval. Okay. What do you think needs to be shown on the efficacy front for not just approval, but also to make a meaningful change in the treatment paradigm here and see broad uptake? Yep. JELMYTO saw a 58% CR rate. It can only be used in about half or less of the patients because they can't treat the ureters, they can't treat tumors more than 15 millimeters. When Surena did the work with infigratinib, he only treated for half the time during the three-month period. Three weeks on, one week off, three weeks on, no more. Saw a 67% response rate, and there were some high-grade and low-grade mixed in there. What was remarkable was out of five patients that were scheduled for nephroureterectomy, that's removal of the kidney, three were spared their kidney. There were some tumors that shrunk down that could be surgically removed. There's actually a high benefit for just seeing responses, whether they're CRs or PRs. When we did market research, CR rates that were just sufficient for approval, call it 30%, physicians indicated they would try oral in nearly every patient. If you think about it, if you're getting even modest CRs, lots of PRs, any patient that's seeing any benefit will stay on this as long as it seems to be reducing their tumor, sparing their kidney. There's a variety of data sets that could be very compelling here. I think the IR NMIBC data set we'll have in August, again, this is the same urothelial cell with the same mutation, it's just in a different anatomic location, could be very meaningfully de-risking for how you might think about the upper tract. We're not constraining the tumor size, so there can be more tumor burden in the upper tract for this study. We don't think that would be a meaningful impediment, especially if patients are able to just continue to stay on drug and potentially see tumors shrink over time. Understood. You suggested that the NMIBC data could be a key de-risking event for Upper Tract. I don't know, maybe you could elaborate on that. In particular, would you expect the doses to be different? Is there a different sort of tolerance for adverse events or safety? Can you push the dose in upper t ract relative to NMIBC? How are you thinking about all this? We do think we could push the dose a bit for upper tract. There could be a better tolerance to deal with AEs because you're staring down the full-scale removal of kidney, which would be irreversible and could have a lot of downstream consequences. We're not constraining the tumor size, so we actually want the drug to chemoablate, which could be different than the NMIBC setting in an adjuvant. You may want a little bit more drug on board, which is why we're testing 60 and 80 in the UTUC setting versus the 50 and 60 in the NMIBC setting. Okay. That makes sense. How large do you think the UTUC market opportunity is? Maybe discuss the IR NMIBC opportunity as well? Yep. I know we're going to get quick on time here. Two key points. When we think about UTUC, I think about the levers we could pull that sort of differentiate from where JELMYTO is today, which is selling maybe $120 million-$150 million. Price point there is about $25,000 per dose. They do six doses spaced one week apart, so it's about $150,000. The price points that you're seeing in the bladder-sparing, Anktiva and Loxo Oncology, are getting you to kind of four to five times that. That could grow the market to half a billion just from premium pricing for a novel oral therapy. You think about the ability to treat a patient population that's probably at least double what JELMYTO is actually indicated for. Patients that have lesions in the ureters, patients that have lesions greater than 15 millimeters. That really gets us to blockbuster potential, where it expands from there as patients that may choose on, not just for the first year, but for second year and third year, to spare their kidney for a long, durable treatment. That's really exciting, but by far and away, NMIBC is bigger because the population's nearly 10 times as large. I like to quote that market that osimertinib sees, which is a similar patient population. osimertinib sees 33,000 EGFR-positive lung cancer patients in the U.S. That's about the same size, the 35,000 EGFR-positive IR NMIBC patients. The durability for osimertinib is about two years. We would look for about two years' worth of treatment. That drug, osimertinib, is doing about $7 billion in sales. There's a huge market potential when you have these many patients willing to take therapy to avoid the unmet or to overcome the unmet need, which is urethral violation and procedural burden. Yeah. Pretty sure most people haven't made the osimertinib connection yet in terms of the market opportunity. Glad you brought that up. As always, Todd, thank you so much for your time. It was a great discussion. Thanks to everyone for logging in, and have a great day. Thanks, Tyler.