Hello, everyone. Welcome to our Fireside Chat with Tyra. My name is Li Watsek, a biotech analyst at Cantor, and very excited to have Todd Harris, CEO of Tyra, with me today. Todd, great timing. You guys just announced your intermediate N MIBC data this morning. Congrats. I would love to maybe have you walk us through the story a little bit before we dive into the details. Wow. Are we going all the way back to the beginning on this story here? Yes. Sure. Look, Tyra's a company that's focused on precision medicine, and we make our own drugs. We have an in-house SNÅP Chemistry platform. It's structure-based drug design. And we made dabogratinib from scratch, something we kicked off nearly seven years ago. We've come a long way. And absolutely thrilled today to be sharing the first proof of concept of a potential oral FGFR3 selective drug in the intermediate-risk NMIBC setting. This is part of our broader strategy that we're moving forward with dabogratinib. We're pursuing two urothelial indications, NMIBC. We're pursuing upper tract urothelial, a rare disease with a similar lesion type in the urothelial lining, but in the kidney and the ureter. And we're pursuing growth disorders, including starting with achondroplasia. What's so meaningful about the data today is this is where the majority of the patients are with unmet need that could benefit from a drug like this. This will be our biggest indication. For the first time, we're showing this proof of concept that with dabogratinib, we have a drug at 60 mg that could support chronic dosing to suppress FGFR3 orally, that has the activity we were hoping to see in terms of, we did a marker lesion study and in terms of seeing the activity with those lesions shrinking, and that has the convenience of an oral. Really underline that last point, which is so important because it's a competitive space, but all of the competitors are continuing a paradigm of urethral violation in order to get their therapy in. Patients are already voting with their feet today. 70% are opting out of an effective maintenance adjuvant treatment via induction maintenance chemo. Despite that reducing their recurrence risk by 44%, 70% of patients say, "I would rather wait to recur than have all these catheterizations." An oral for the first time gives this patient population the hope and promise that they could control their disease with a simple at-home daily pill, and it's a complete game changer. The data we shared today shows proof of concept and a high likelihood of success as we move into phase III, which is the next step. We're going to be aligning with FDA. I think worthy of talking about that because we now have really a set of data that I would say is strongest in the space for predicting our potential success in phase III, let alone predicting what I think would be a very successful commercial product, potentially first in line. This is a $5+ billion market opportunity. I would say the profile we have is leading the way as the likely first-line choice for physicians when they think about what really moves the needle for their patients that are over-instrumented and overburdened. Maybe let's start with the data this morning. Obviously, it's quite encouraging that you guys show some really nice data supporting an oral therapy for intermediate NMIBC patients. As you alluded to, Todd, I think the treatment burden for this patient population is really the procedure, right? With the oral therapy, you have the convenience factor. Maybe just give us a quick highlights of what you showed from the phase II data. Yeah. And just to underscore that point, we asked in our physician survey, and we shared some of this data, about what the highest unmet need is in this patient population. And the number one, 75% of physicians said it is the procedural burden, it is the repeat catheterizations. That is the unmet need. It is over-instrumentation and procedures. These lesions can get cut out, but the process of cutting it out, that surgical burden is high. And yes, you can catheterize and put chemo in there and see lesions disappear, but it is how can you get to an outcome with something that is not so burdensome on the patient? And that is really the vision and the goal for dabogratinib. What we were able to show, this was a really important study that we designed. We wanted to get to an answer quickly. We wanted to get an answer of what is a sufficient dose that we could use in the adjuvant setting to keep tumors from coming back. To answer that question, we had physicians leave a marker lesion or lesions behind in the tumor. We had them take drug for three months or longer, and we evaluated, did the tumor shrink 50% or more or disappear? And when we looked across all the patients, we had two doses, 50 mg and 60 mg. And we evaluated both those that shrank completely and those that shrank 50% or more. We saw a clear dose response. At 60 mg, 79% of patients had a response. That means that their tumor was shrinking either 50% or more, or the tumor was gone. We had a 54% CR rate initially, but then migrating, sorry, 57%, migrating to 64% because those PRs start converting to CRs as we follow these patients. And that is really an extraordinary outcome, and it is the overall response that really matters in this adjuvant setting. Now, one of the things in the expectations going into this data set were around how would we compare with the only other oral that has attempted this. That study was a study called THOR-2. It was oral erdafitinib. It was done at a single dose. It was done with marker lesions, but only one marker lesion was left behind. We actually evaluated patients both with one marker lesion and multiple marker lesions. What we saw was that when we looked at the patients with the single marker lesion, so the comparable study, there we actually have 100% ORR and a 75% CR rate. That is exactly in line with what THOR-2 was showing at a similar timeframe. That gives us the strong signal that we are suppressing FGFR3. With the oral, we are getting the best possible outcome that can be seen. You cannot beat 100% ORR. That now allows us to anchor on the dose as at a go-forward dose in the adjuvant setting. Now, we had additional information that we learned from this study, which is multiple marker lesions, and we saw that the multiple marker lesions were harder to debulk and get to either a PR or CR. That is more indicative of using the drug in an ablative setting. While there is one approved drug, UroGen, to be used for ablation, the vast majority of the market is oriented around a procedure, TURBT or fulguration, to remove tumors, followed by maintenance. All of the go-forward programs here, and there is five of them, are adjuvant phase III's. That means all tumors removed, no marker lesions are left behind, and you are using intervention to prevent recurrence. In that setting, where it is the biggest market, this single marker lesion is our clearest evidence that 60 mg can be a highly effective dose. Now we can take this data, go to the FDA, and move forward with our planning on the 60 mg dose. But we also shared something in our presentation today, and I think it is where really investors should focus on next, which is what is our probability of a phase III success? We now have the richest set of information to predict the potential success, not just the treatment effect, but also the effect we might expect on a placebo, leveraging some important information that was shared in the last few months from Dr. Meeks at AUA. You can now construct really a scenario for what is Tyra's success taking dabogratinib at 60 mg into phase III and compare that across the other programs. All of the other programs did not run phase II's except for J&J. There is really no information to predict success there. When you look at J&J's phase II, they did run a successful phase II with TAR-210, but the treatment duration there is only going to be for 12 months. Both in the phase II and the phase III. In the phase II, when they shared the data, you could see the degradation with recurrence after patients came off of TAR-210 happening pretty quickly. When you start to model out what might they do over 24 months compared to what we could do, it's clear we have an opportunity to win on efficacy for chronic durable efficacy with a daily oral for these patients. That sets us up with a potential best-in-class profile in a $5+ billion market, where it's clear that the patient preference will be for an oral. This is a remarkable step forward for patients and for the industry. I think doing that analysis now of what's the probability of success, what does the phase III look like for Tyra, how does this market open up for Tyra, is really where we want investors to start focusing because the patients are excited, the physicians are excited, and I think what investors will appreciate is that there's a really, really big market there. I wanted to follow up on this single marker lesion versus multiple marker lesions. What was the rationale for you guys to include patients with multiple marker lesions in the study, given you mentioned how J&J only included single marker, and just from a tumor burden and response perspective, obviously, you've learned some very important lessons here. As we think about phase III adjuvant setting where the tumor burden may be even lower than phase II, how should we put together the data set just from probability of success perspective? Yeah. Okay. Let's start with the multiple marker lesion. Before we ran the study, no one had done an experiment like this before. We now have an answer really to add to the space that's quite meaningful, and what it tells us is when we're comparing to what was done with THOR-2- single marker lesion, we have the same on-par activity, which we've talked about all along. On-par activity to THOR-2 with excellent safety profile would be lights-out data. That's what we're seeing. The multiple marker lesions almost gives us a second study within this SURF302 study to look at early indication of ablative. This is exploratory and upside, and we're going to test a 70 mg dose given what we saw, because the one area where there was more non-responders was for patients that had multiple marker lesions. If you're using the drug to ablate, of course, you're going to want enough drug that you're going to see a good response across multiple marker lesions. So in an exploratory analysis, we're going to look at 70 mg. We also need to talk to the FDA to understand is there a path forward for us in ablative. They were pretty clear in the UroGen doc for us and others that there was some stringent requirements around ablative path forward. Adjuvant randomized studies have obviously been the preference where everyone's going because that's the bigger market and there's a clear regulatory path, and that's where we're going to go with our 60 mg dose. If there is an opportunity for ablative, and we'll talk to FDA, we'll evaluate this higher dose. That's upside opportunity for those patients that want to avoid surgery and just use a pill to debulk their tumors. There could certainly be an additive market for that. But really the main market we see is in the adjuvant setting we're moving forward with in the phase III. What about durability of response? Obviously, you guys show pretty nice response data and you've seen some deepening of response from three months to six months. How confident are you that you're going to see CR durable response as we go into year one, year two? Yeah. All we can do is look at the same data that everyone else can look at. Until we follow our data out for 24 months, we wouldn't have that answer. But we do know by looking across our data, looking across the TAR-210 phase II, looking across THOR-2 with oral erdafitinib, that any patient that achieved a CR and stayed on drug, the durability has been 100%. It's a phenomenal outcome. We talk about durability from all of the installations that are advancing into phase III. All those degrade over time. 100% durability. You can't beat that, of course. Is that the expectation? Every single patient, 100% durability up to 24 months? We just need to follow the data, of course. But I think the expectation should be and is durability should be excellent. Mechanistically, if you keep the pressure on FGFR3 with an oral pill every day, the tumors appear to not grow back. Even if you put the pressure on with the pretzel, they appear to not go back. That's really clear in the data. Not only that is we know when you take the pressure off from the THOR-2 and TAR-210 studies, patients recur pretty readily, and it's the most recurrent low-grade intermediate-risk NMIBC lesion type is the FGFR3 positive. It happens pretty readily. You're going to want to keep chronic suppression. And right now, we have the short-term data CR response rate. Then, when we go into phase III adjuvant setting, obviously, that's a very different endpoint, disease-free survival, and I believe you guys are going to be looking at 24 months. So maybe walk us through the math. I know you guys have done some modeling, but I think it will be helpful for investors just to put the pieces together. Just tell us why you're so confident that your phase III will be successful. Yeah. So we'll look at a disease-free survival endpoint. Others are looking at recurrence-free survival. Those are very similar. Disease-free maybe encompasses lesions maybe outside of the bladder, but I think in this disease setting, those are expected to likely be similar, if not the same. It will look at event based. It's not necessarily that the primary endpoint is 24 months or 12 months, it's when you've accumulated a sufficient event to win on a hazard ratio. But patients will be on treatment in the study, like our phase II, we would plan for a phase III with 24 months of treatment. As you look across all these studies, there'll be patients that are out past 24 months and patients less than when they read out the primary analysis. Secondary endpoints would be 24-month DFS, 12-month DFS, so we'll look at those as well. But I think your question is excellent because reframing the conversation to what really matters is the probability of success in phase III based off of the body of evidence and data that we have and others have today. We have a compelling case now with the data we have, combined with, for example, Dr. Meek's data on the 16-month median RFS for the FGFR3 positive IR-NMIBC. We can really start to construct the likelihood of success for a DFS endpoint. With all of the other companies not having run a phase II- only we and J&J have the information to actually start to predict success in phase III. If you look at J&J, they've got the 12-month data. Now you can add to it the degradation you might expect after 12 months from the recurrence starting to happen based off of Dr. Meek's data. Now you can look at our data, and we put a few scenarios up. This is a model. Yeah. The point is that even in the most conservative assumption, it would be hard not to win with the data that we're sitting on today at 60 mg. We would look at that 64% of patients at risk and take the CRs and the PRs, provide an estimate of durability, and ultimately then project out DFS. It's a relatively straightforward scenario. If we take our THOR-2-like criteria, single marker lesion, the results we're seeing so far, a simple model with conservative estimates gets you to a disease-free survival of 80%. Even if that DFS were to drop all the way down to 55% That would be a hazard ratio of 0.6, and we would win on a phase III. We'd be able to provide patients an oral option that's efficacious in an environment where literally 70% are not taking the options that are efficacious because they don't want the catheter. That's going to be a huge win. We've got a variety of scenarios where we can win here, and we've got really the most robust data set to start to predict a win in phase III. Then fast-forward from that, I think we're starting to share this market research with patient data, with physician survey data to highlight that this would be a first choice. Be a first choice for physicians to give over TAR-210 in a variety of different efficacy scenarios. It's clearly the first choice for patients who are looking to have the ability to take the pill in the privacy of their home and to start to control their disease without having to expose themselves frequently at the urologist office to get their treatment. For the phase III, Todd, you guys have decided to move 60 mg dose, but on the other hand, you're also testing a higher dose, 70 mg. I understand the purpose of that is maybe there's an upside case that you may be able to pursue ablative setting. If the data there look good, is there a scenario where you might be able to add a 70 mg to the phase III adjuvant study? Yeah. It's really clear to us 60 mg is our dose because you can't beat 100% ORR. We're not looking for tumors to shrink faster. We're just looking for tumors in a maintenance scenario to not regrow. If all the tumors are shrinking, that's the signal for adjuvant. We don't want to increase the dose for the same efficacy. We want the dose that's clearly efficacious. We have the dose response between 50 mg and 60 mg, and we can't beat 100% ORR when we move to the adjuvant setting. That 100% ORR is what was seen in a single marker lesion, the comparable data set to THOR-2. For ablative, as we talked about, different equation. You may need more drug to debulk tumors. We've talked about that already in the UTUC setting, which is why we tested the 60 mg and the 80 mg dose. The path forward for the big market opportunity in IR- N MIBC is not ablative. It's adjuvant. We can't beat 100% ORR. The data that we have today give us a very strong signal. Now, what will we learn before we launch the study? Well, of course, we'll have another 15 patients at 60 mg. We'll have durability data, right? Yeah. These data continuing to mature in line with exactly what we've seen, we would have full confidence that 60 mg is the dose. Okay. I want you to talk about safety. Obviously, Todd, that's very important factor in this patient population, especially if you think about our therapy, chronic dosing. Maybe just put the data into perspective for us. How does it compare to J&J's erdafitinib and then some other intravesical therapies that are in development or approved? Yeah. How does this profile Yeah compare to the others? Yes. Yeah. You have got to take a step back and understand. We shared some new information today from EMR data from UroGen. 70% of patients are opting out of a proven effective therapy in the guidelines because they do not want the repeat catheterizations, and they would prefer to wait to recur and take the procedure. Every single other product that is in development in late stage continues this paradigm of urethral violation to try and maintain treatment. Urethral violation to ablate or remove tumors. Sure, that is a paradigm that many patients are understanding when they recur. But urethral violation to suppress a signal and maintain a response is really unproven in the marketplace. 70% of patients are not willing to do this, and every treatment paradigm continues this. This is where the oral profile changes the game, changes the paradigm for patients. Now they could be offered a pill once a day with the tolerability profile that we are seeing that supports chronic dosing to maintain control over their disease. And when you need to chronically suppress FGFR3 to prevent recurrence, that is obviously the first choice and the first option. AE profile, no discontinuations or reductions at 60 mg, very small amount of interruptions, and really just a pristine profile in terms of what we are seeing. No ocular toxicity, no FGFR2 type tox you might see from a pan-FGFR inhibitor like oral erdafitinib, which would be mouth sores or PPE or nail tox. No hyperphosphatemia. All of those things washed away, and we have just this excellent profile. The number one AE that we are seeing is grade 1 fatigue. Going into this, we were evaluating in this elderly population, what might we see in terms of grade 1 fatigue? If you look across, for example, all the XTANDI studies, the placebo arm would read out 20%-40% grade 1 fatigue. We are seeing something in line with placebo as the number one signal here w ith this drug. The feedback from investigators is excellent on the durability for chronic dosing here, and we've got the activity now to showcase that this could be a real game changer in a phase III adjuvant setting. How confident are you that some of the grade 3 events that you guys observed in the study are not related to the drug? Yeah. You're going to see grade 3 events in an elderly population. At the 60 mg dose, we had three grade 3 UTIs. There's no mechanistic link to this drug in UTIs. These patients get grade 3 UTIs because they're being over-instrumented as part of the treatment paradigm. At the 50 mg, we had two grade 3 events. One was a grade 3 rash. As soon as the patient came off of drug, it actually resolved with interruption and some steroids. We look across the 172 patients treated. We haven't seen that grade 3 rash before. So this is a one-off in this one particular patient. Even at the higher doses, we don't see a growing signal around a rash that showed up at much higher doses we did test in the metastatic setting. So generally, that's one that really isn't of significant concern. The ALT, AST elevation we saw at the 50 mg dose, that was grade 3. That patient had no elevations in ALT, AST on drug, and then for a UTI, they began taking Macrobid and immediately saw a grade 3 spike. Macrobid was being taken for their UTI. It is a known liver toxic agent, so that became a complicated case that we discontinued. Otherwise, the ALT, AST increases across both the 50 mg and 60 mg dose didn't raise to something that shows up on our HR because it was less than 10%. Any risk of cumulative toxicities? You guys have some clinical experience with this drug in metastatic setting, but also in intermediate risk. That's right. For this study, there's been a patient on drug for 15 months. For our metastatic study, several patients that remain on drug past two years. No, we just haven't seen anything appear from a cumulative tox. Everything that might show up as a key signal, shows up within the first cycle or two, the first 30 - 60 days. That means this data set is actually quite comprehensive, because the median time on treatment was over three months for all the patients reading out on safety. How comfortable do you think the community urologists would be with a drug like this in terms of safety? Do you anticipate any monitoring may be required? At this point, until we run a randomized placebo-controlled phase III, the need for any monitoring could obviously be decided there. We are talking to the investigators. I think for those of you who heard Dr. Silva on the call today, they are loving the experience their patients are having on this drug. Many of these physicians did do the oral erda study, and it is just simply a night and day experience right now. I think there is a strong enthusiasm that the profile that is emerging here from everyone that we have shared it with to date really would support wide use and chronic use in this large patient population. Maybe just a word on the read-through to the UTUC study. Yeah. We were excited to share our first patient that came on study who had their three-month scan at 60 mg, had a CR and no AEs. Why that's relevant to the data disclosure today is, remember, this is a urothelial cell type that gets the FGFR3 mutation and starts to grow out low-grade lesions. Whether that happens in the bladder or in the ureter or in the kidney, it's still sort of the same type. It's just an anatomical different location. This adds to the body of evidence, but more importantly, it's an early indicator, at least one of the doses, and we need to recruit more patients and evaluate more doses, is having the response that we're seeing. So it helps get a read-through from our NMIBC data today towards UTUC. UTUC is another blockbuster indication. It's a rare disease, but the unmet need's higher because patients face kidney removal, nephroureterectomy, and no good treatment options. It's just hard to intervene surgically in removing these lesions. High recurrence tumor, typically, or the kidney typically comes out. This is an opportunity for us to have a second blockbuster indication. Obviously, our Dabo 3x3 strategy talks about each of these plus achondroplasia. I think folks that were paying attention today now see, oh, actually de-risked two blockbuster opportunities with this drug with some of the data we're sharing. We'll be able to get the data next year in UTUC. Yep. The key next step there is select a dose. Do that as quickly and effectively as we can so that we can move into the expansion portion in this study, which has registrational intent. Okay, great. Thank you so much, Todd. That's all the time we have. Thanks, Li. Thanks for the discussion.