Hello, everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst at H.C. Wainwright. It's my pleasure to welcome you to our HC Wainwright at Home series. Today we have Tyra Biosciences and from the company. I'm pleased to welcome CEO Todd Harris and CMO Doug Warner. Thank you both for joining us today. Thanks, Mitchell. It's great to be here. Thanks for having us. Great. Yeah, it's our pleasure. We're going to have a fireside chat, cover all the different bases that you all are working on. To set the stage for investors who may be catching back up on the Tyra story, or those who may have not been familiar with the Tyra Biosciences story, could you just give a brief introduction in the current pipeline initiatives that you all are focused on? Great. Let me start us there. Tyra Biosciences, it's a discovery and development company. We have two active phase IIs with our lead compound, which is an FGFR3 selective inhibitor. They're in two really unique and exciting and large opportunities. One in bladder cancer, specifically where we're advancing it right now is in the intermediate risk FGFR3 positive non-muscle invasive bladder cancer setting. FGFR3 positivity is quite high in this setting. It's 70% - 80% of all patients. It's the largest segment of bladder cancer patients, actually the intermediate risk segment. There are nearly 700,000 patients living with bladder cancer today in the U.S., a really exciting opportunity there. Achondroplasia, where FGFR3 alterations drive the skeletal dysplasia condition that is commonly called dwarfism, leads to not just short stature, but very serious complications and health complications throughout life, like the need for surgeries on the foramen magnum, spine, and other ways. We have a drug that we've made in-house through our SNÅP chemistry platform. It's highly selective for FGFR3, which sets it apart from everyone else who's done development here. It's demonstrated proof of concept now with really compelling efficacy in a late-line cancer setting and really compelling tolerability and safety. We do have other compounds advanced in the clinic as well, TYRA-430, all homegrown molecules. We maintain a really active discovery shop in addition to that development activity. Great. Thanks. With dabogratinib in NMIBC, TYRA-300 now renamed to dabogratinib officially, that's exciting. In NMIBC, starting there, one of the major opportunities for you all, can you please just outline your trial in NMIBC and how you're deciding to blaze ahead with that indication as a priority after the metastatic urothelial cancer data from last year? Is this kind of the lead priority, or would you characterize the lead as multiple things? Just tell us where this sits in terms of your priorities. Yeah, let me kick it off and hand it over to Doug. We love both our children equally. These are compelling, exciting, very different opportunities when we look at intermediate risk in NMIBC and achondroplasia. What joins them together is just simply the science. These are FGFR3 overactivity or constitutively active conditions. We've made a very selective, oral, bioavailable, very well tolerated FGFR3 inhibitor. It's just only natural to be pursuing with this drug both the opportunities. We're excited about them equally. We're advancing them equally forward today. There are obviously nuances and differences as we get towards commercialization. The plan is to prioritize really both of these separate indications. Doug, do you want to talk about the study design for the NMIBC study? Yeah, it's a phase II study that's enrolling patients with low-grade intermediate risk NMIBC who have activating FGFR3 gene alterations. Patients are randomized to a dose of dabogratinib at 50 mg or 60 mg q.d. It's a marker lesion study. The primary endpoint is three-month complete response. Secondary endpoints include duration of response as well as time to recurrence. The study does have the option of opening up a third arm based on the data that we see in the primary two arms of the study. Great. Just thinking about the study design in terms of the randomization to the daily dose of 50 mg versus 60 mg with a possible third cohort, could you walk us through how you got to those dose levels from the PK/PD bridging from the SURF301 study? What target coverage are you expecting to achieve at those dose levels? Yeah, Mitchell, let me start us off. It's a really great question. It's one of the most common questions we get from investors. We stand on the shoulders of giants in science. I want to give great respect to the folks at J&J that have done really meaningful development with erdafitinib, a pan-FGFR inhibitor. That is a drug that's approved in the late-line setting. They did a series of dose exploration PK/PD work. They even explored the intermediate risk NMIBC setting. They explored it at a lower dose, which was driven by the need for better tolerability with that drug. It in the end wasn't sufficiently tolerated. What they highlighted there is that target coverage could be different between metastatic urothelial and NMIBC and drive compelling results in both. They saw at a low dose an 87% CR rate in an intermediate risk non-muscle invasive bladder cancer chemoablative study. That 6 mg dose was actually explored at NMIBC and not as effective as their 8 mg- 9 mg that was ultimately on label and pursued. The difference in target coverage there was a difference of 8 mg- 9 mg covering the IC90 of the target fully versus their 6 mg covered an IC50, not quite getting to IC90. There is evidence in their preclinical models that they were able to see bladder accumulation. I spent a lot of time talking about erdafitinib and why, because it's really our best benchmark for understanding FGFR3 engagement. We can now take the multiple doses that we studied in our phase I. What we learned there is that once we got to 90 mg, we were able to show that IC90 complete coverage generated at 90 mg or above. The data we shared in the fall, over 50% ORR and really great tolerability. We also had 10 patients treated at a 60 mg dose. We were able to track that PK and note that it had a very similar exposure and predicted target engagement as erdafitinib 6 mg dose, where they were very successful in this setting. That really allowed us to anchor there on the 60 mg dose. There were quite a few patients in that early erdafitinib intermediate risk study that actually dosed down to 4 mg as well. We felt like we should also explore some lower doses. We want to optimize tolerability, safety, and maintain efficacy. That was really the basis for that selection. Finally, when we look at the doses, patients treated at 60 mg or below, and we had about 10 patients treated at 60 mg, 10 patients treated at 40 mg, and a couple of patients treated lower than that, we saw a really pristine safety profile. The things that show up when we really push the dose in the MUC study were we started to see some diarrhea kicked in early, which was very addressable with Imodium. We saw some AST and ALT levels that were largely low grade and asymptomatic. When we look at the 60 mg in particular, much of that goes away. Especially, there was almost a complete lack of the AST and ALT elevations. If there's any diarrhea, we would anticipate it would be very modest. It was a very low rate at that. We feel like, and as we shared this with urologists, that that profile of safety is absolutely a winning profile. We wanted to make sure that we had two shots with the 50 mg and 60 mg, see how we did on the efficacy, and ultimately choose the most efficacious and well-tolerated dose to move forward. We do have an option to explore other doses if for any reason we don't see what we anticipate based off of all of that pre-work between what J&J did and what we did. We're confident we're pretty close in the zone where we want to be. We think it'll be a highly responsive disease. These are relatively small tumors. They tend to be largely driven by FGFR3. There's less co-mutations in the metastatic setting. The responsiveness we anticipate being good. We'll have some data that we plan to share, the first cut of early data in the first half of next year. Great. Yeah, and I imagine the two doses satisfies the Project Optimus requirements from the FDA as well. That's exactly right. Yeah, it's an important thing to do. Yes. Yeah, yeah, makes sense. OK, moving to the data that first looked at the three-month CR data that we get next year, can you set the stage for how impactful that readout is? What three-month CR rate and duration of response would drive a go/no-go decision to expand or to look to a registrational study? Is this benchmark, the 70% CR TURBT rate, really the focus at three months, or is there a different time point? Just trying to understand a little bit more about the benchmark for efficacy and what we should look for this initial readout. Yeah, let me kick it off. If Doug wants to add, I can hand it over to him. We started off with a panel, some of the world expert KOLs, urologists. The clear feedback they had for us was an oral drug is such a game changer in potential convenience for the patient that even a modest CR rate up front, call it 70%, would likely be very attractive for them to use. These urologists and patients, they're focused on having options. This is going to be a setting where there will be a ton of options. It's also a setting that's very different than the way that we typically think about oncology because the five-year survival in the intermediate risk setting is nearly 95% for these patients. The risk of progressing to a more advanced disease or death is actually quite low. The unmet need here is a function of cost, and it's a function of the experience. A friend of mine came out and talked to our company at an annual event we had last week. He has intermediate risk non-muscle invasive bladder cancer that's FGFR3 positive. He was diagnosed a couple of years ago. He had a recurrence about six months ago. He talked about his experience. I think there was a really memorable moment as there was some Q&A with him where someone asked, how many times have you had a catheter placed up your urethra in the doctor's office in the last two years? He thought about it and then answered 36. Thirty-six office visits with a very painful procedure to put a catheter up the urethra. In most of those instances, he had to stick around for about four hours to put chemo and install it in his bladder, which was something that was done on a monthly basis, all for the intermediate risk NMIBC diagnosis. Now he just wants to be cancer-free. That risk of potential death from this disease is low, but it's always looming in his mind. The idea that a doctor could essentially diagnose and send that patient home with a prescription to just take TYRA-300 every morning for the next two years plus and avoid those 36 visits to the office, the six hours of chemo installations, it's a total paradigm shift. Patients get it. When you spend enough time with the urologists and they understand what we're doing and the profile of TYRA-300, they start to get it too. It's going to be great to have options and intravesical options. I think surgery will ultimately still play roles in this setting. This is something that will be highly attractive, even if it is a modest, and I say modest, a 70% CR rate that appears to continue to be durable out to 12, 24 months and beyond. The durability we anticipate being pretty solid. If we're able to chemoablate that tumor up front in the first three months and then maintain that pressure day after day, we think the durability of an oral is going to be great. The key is going to be tolerability. We feel really good about the profile of 50 mg and 60 mg and just how tolerable of a drug that's going to be if we can get to the efficacy that we hope. I think that's going to be a huge motivation coming out of a phase II where we show that around urologists starting to get on board with the first oral opportunity in this space. Yeah, that's very helpful. I mean, especially I know we have talked about how this is an opportunity for a patient to try this oral before they even go on to TURBT or another more invasive procedure. That also kind of gives you a little bit more room for how efficacious a therapy can be like this. Thinking about the readout again in terms of measuring a CR and the marker lesion logistics there, how are you standardizing the marker lesion assessment and what imaging or biopsy confirmation would be required at the three-month mark to call it a CR? Will these be confirmed at this point? Yeah, Doug, do you want to take this one? Sure. Patients must have at least one marker lesion. The measurement of that is down to 3 mm up to 12 mm, and that's measured with a standard resectoscope. A complete response is a complete visible resolution of the lesion, in addition to negative cytology and a negative biopsy if it's indicated. Not all patients would require a biopsy. OK. Very helpful. To identify the right patients for the study and for the drug, 70% FGFR3 prevalence in this population, what's the plan in terms of screening for FGFR3? Will testing occur both in the academic and community setting? Is there any difference in that? How will this shape up in the real-world setting to find these patients? Yeah, Doug, do you want to take that? We're using the same platform to measure, evaluate FGFR3 activating alterations as J&J is using in their development program. We're collecting urine at baseline and actually collecting it throughout the study as well. It is that platform or urine-based test that is quite easy, as you might imagine, to collect and then follow throughout the course of therapy. I think that would be consistent with the ease of use in both academic and community settings. OK. Got it. Very helpful. Beyond FGFR3 status, will you be collecting other co-mutations, ctDNA, and other pharmacogenomic data that could help identify who is more likely to achieve a CR or recur? Yeah, we will be collecting at baseline, as you mentioned, ctDNA and then throughout the study. We'll be evaluating, we'll be doing complete genomic profiling as well as looking at changes from baseline. We're also going to be looking at tumor-derived exomes at baseline and throughout the study. If tissue is available, we will also be looking at complete genomic profiling as well as evaluating transcriptional activation of FGFR and FGF associated genes. OK. Got it. Great. For safety in SURF301 at and below the 60 mg dose level, the FGFR-related AEs looked kind of mild, largely grade 1 to 2. Which AEs are you focused on in this population at 50 mg - 60 mg? What are the thresholds in NMIBC that may be different than what we saw in the metastatic setting? Let me start. When we push the dose on a drug like this, what we saw, pushing it well above the 60 mg, as I mentioned, is diarrhea and then AST/ALT increases. The majority of this is low grade, even at the highest doses for diarrhea, high resolution with Imodium. The AST/ALT were largely asymptomatic, low grade. When we look at 60 mg, we had no AST increases. There was one patient out of 22 patients treated at 60 mg or below that had a mild ALT elevation that was grade 1. We actually have highlighted that on re-review of that lab data, their highest ALT measurement was actually a baseline scan. Even though it was called ALT increase, that wasn't quite exactly what was seen. We've queried that. Nonetheless, a very low rate of low grade ALT/AST, that would be not unlike a statin, for example, which urologists would be very comfortable prescribing. A blood draw is a very simple thing to do in an in-office procedure if it really did ultimately require that. Not saying it would, we'll have to see what the data say. From a diarrhea perspective, even the diarrhea we saw at 60 mg or below seemed to have a different character or nature. It wasn't necessarily coming on as early, maybe several months into the treatment regimen we saw it, which possibly related, but also begs the question how related maybe was it to the drug as well. We'll have to evaluate whether this is a real, how much of an AE this is at the 60 mg and 50 mg dose. No discontinuations or disruptions. No hyperphosphatemia at 50 mg and 60 mg. That's a really clean and important profile when you compare it to the pan-FGFR inhibitors. Even at the low dose with erdafitinib, I think it was nearly 100% hyperphosphatemia at that 6 mg dose. OK. Yeah, no hyperphosphatemia at 50 mg to 60 mg. You wouldn't anticipate any prophylactic binder use or anything at this dose level. Monitoring is fine at this point. Absolutely. Yeah, we anticipate that should be just fine. Great. OK. Moving on to competitive context, erdafitinib, you'd mentioned the 83% CR. They had a notable tox profile. Could you talk about how you expect dabogratinib selectivity and daily dosing to translate into real-world persistence and adherence to therapy versus oral pan-FGFR or intravesical therapies as well? Yeah, the oral pan-FGFRs, you just have to look at the label to kind of learn what's going on. One in four patients dose reduce or discontinue oral erdafitinib because their fingernails are starting to peel off and become extremely painful. One in five patients is dose reducing because the sores in their mouth are becoming pretty excruciating. Nearly as many are coming off because of rashes in the palms of their hands and their feet and some eye conditions as well. We know that the AEs I just highlighted are driven by FGFR2 inhibition. We know that because of relays, a highly selective FGFR2 inhibitor really exacerbates those same AEs at similar rates in their studies in intrahepatic cholangiocarcinoma. We've validated in our hands now the massive reduction down to single digits of nearly all of these AEs in patients that would otherwise be 50%, 60%. Our confidence is really high that that selectivity profile we built in from the beginning is playing out with the clinical manifestation of AEs. When we look at, again, the 60 mg dose, it even cleans up that profile further. When you're thinking about positioning versus TAR210 on setting of care or patient convenience, how do you see that landscape evolving? Yeah, TAR210, I think it's a really exciting program. I anticipate they're going to get some really nice data out of their MoonRIS-1 study, which is an adjuvant study. I think they would also be wise, and I think they are, to maybe do a chemoablative single arm alongside of that because I think that would be a really interesting use. They seem to have some activity there in the intermediate risk setting. I think the really important thing to highlight here is this should be efficacious. That FGFR3 engagement locally delivered has shown really promising POC in phase II. However, it's a device in your bladder that is eluting drug. It's something you're going to feel every second of every day when you have this Pretzel or TAR210 installed. Not only that, a lot of folks talk about the need to just avoid systemic tox, and that's going to be the priority for the urologist. The reality is with TAR210, every time you take in and out the Pretzel, you typically use some prophylactic anti-infectives. Now you're introducing systemic tox on top of this procedure. You can have diarrhea from prophylactic anti-infective use here. The idea that this is really clean and pristine from an AE profile, in addition to the pain, blood in the urine, and just feeling this urgency all the time, it's not necessarily going to be a walk in the park. I think it's better than TURBT and sitting in that office every month and having chemo pushed up in your bladder for four to six hours. I think it's a huge step forward there. When you compare that to a well-tolerated oral that you take every day with the systemic profile that we are seeing and that we've seen in MUC, I think this is when urologists really sit down and talk with us and sort of get it, the term we often hear is game changer. I think it will be. It'll be potentially the first oral. It'll be an absolutely compelling option for patients versus all of the intravesical repeat procedures that will be demanded from CG Oncology, UroGen, and just about everyone else that's developing in the space. Great. I want to jump ahead a little bit to the community channel dynamics. We've talked about uro-GPOs. I think that is a rather complex topic. Maybe you can help explain to those who may not be familiar with how some of these drugs reach patients and kind of the model in a setting like NMIBC. Can you just talk about that blueprint for distribution and support of dabogratinib, if successful, and making that easy to prescribe, dispense, and monitor in that setting? Yeah, thanks for highlighting this. It's a really important piece because one of the immediate reactions we often hear from folks is, don't urologists love doing procedures? Why would they give an oral? I think historically, that proclivity for procedures, if you go back 20 years, that was the way their practice was driven. The economics were almost 95% driven by TURBTs, intravesical cystoscopies, and manipulation of the bladder. Fast forward, there's been a big evolution. You mentioned uro-GPO, and they've been a big part of this. The evolution came with the oral prostate cancer drugs, Zytiga, and other drugs more recently, like Orgovyx. These drugs started to replace procedures with an oral format. In an effort to really help urologists maintain these patients in their practice and not just lose them to the academic medical centers, which are even further afield from where these patients live, uro-GPO actually came along to help them, one, learn the management of these orals, but two, go ahead and set up an in-office dispense pharmacy that was licensed by their respective state, and then be a service provider for dropping and shipping that drug, but also commanding the reimbursement and negotiating with pharma on discounts and rebates that then they share with the practice. We're all familiar with buy and bill for procedures, and you can make a spread of about 4% on the purchase of a Part B drug. This essentially allows that same economic benefit in a Part D management because they're sharing a spread back with the practice, but with a really important distinction. In the Part B practice, and if you think about drugs like Immunity Bio and then ultimately J&J, there's very large outlays of cash for these devices. They go into cold storage until the patient's ready to be seen, operated on, or have the procedure. They install, and then they go seek reimbursement with that 4% spread. We hear from practices talk about how they have to withhold partners' checks to be able to outlay the cash for Immunity Bio and other higher priced drugs that are coming along because they're waiting for reimbursement of that 4%. For the oral drugs, it's actually not a working capital issue at all. There's no immediate outlay and then waiting for cash. Actually, uro-GPOs have helped guarantee Part D reimbursement even before the drug is prescribed and even before the drug is really ordered for drop ship, so that they're getting that spread before or even without any need for outlaying any cash. It becomes a really convenient way. As a result, you've seen since 2008, Part B spend or Part B revenue into the urologist's practice has grown from about 5% to about 15%. Out of nowhere, Part D revenue, this is the oral drug spend, has grown to be 15% as of 2021. The uro-GPO folks have hinted this may be upwards of 40% today. Huge driver. They have these in-office dispense pharmacies covering nearly 80% of lives treated by the community urologists. They're not focused on the academic medical center, but 70% or so of patients are in the community. The academic medical centers, I think, have their similar ways and incentives where an oral is going to be very attractive based off of the patient experience as well. All of this comes together to highlight that the market's really well primed for an oral thanks to all the work that's gone into the prostate cancer drugs. On a personal note, we were really pleased to bring Adele Gulfo onto our Board towards the end of last year. She was the one that actually commercialized Orgovyx, which has been a very successful launch using uro-GPOs, obviously using this format to replace Lupron, a procedure that's Part B billed with a Part D drug. She works with us actually quite closely on building out our commercial launch plans and commercial model and market research because this is ready for bladder cancer. No one's done it yet. Because it's the same prescribing physician, it's a model that's ready to go for a drug like dabogratinib. Yeah, it sounds kind of like a plug-and-play situation, especially with having the blueprint, the personnel to get this done. When you're translating that to having a physician test for FGFR3 and when they're thinking about economics, can you just set the stage of how that would look in a practice of when the physician says, hey, this makes sense for me, or is it something that they get in the habit of doing? How does that whole dynamic play together? Doug mentioned the convenience of tests like the prednisone test that we're using with urine. These things turn around very quickly. Given the high proportion of patients that are FGFR3 positive, 70%, it's really a no-regret move on the part of the physician to go ahead, test eligibility, and then prescribe a treatment plan that could be oral if you're FGFR3 positive, but then might look at other options if you're in that smaller percentage of patients that's not and where an intravesical or other treatment might be warranted. Got it. Great. OK, moving on, I don't want to spend too much time on the metastatic urothelial carcinoma setting, but a lot to unpack there. We could spend hours talking about everything in the pipeline. Just briefly, could you recap kind of what we saw last year and contextualize the efficacy and safety versus the pan-FGFR inhibitors such as erdafitinib? Where does that leave you for future potential? Doug, maybe you could speak to the data, and then I could speak a little bit on how we're prioritizing this among our other opportunities going forward. Sure. As Todd alluded to before, we saw a partial response rate of 54.5% in the 90 mg and above dosing, and the safety profile was dramatically improved compared to erdafitinib. We're talking from 70% nail toxicity in erdafitinib to one case in our trial, similarly with one case of stomatitis out of 15 patients. FGFR2 toxicity was just dramatically lower. It was really a paradigm shift. FGFR1 toxicity, hyperphosphatemia, was also dramatically lower. We had two cases out of 15, so 12%-13% hyperphos rate. There's only one patient that required a phosphate binder. As Todd alluded to before, reading through to the lower doses, we presented the phosphate data, and we essentially saw no change in phosphate levels at the 40 mg, 60 mg, and even the 90 mg dose when you look at the data itself. Overall, efficacy tracking at that data cut above what erdafitinib showed, obviously a small data set, but clearly proof of concept that targeting FGFR3 in particular can result in a substantially lower rate of FGFR2 and FGFR1 toxicity. We did have, as Todd alluded to, diarrhea lower than what we saw with erdafitinib, low grade primarily, and then asymptomatic LFT elevations that are consistent with pan-FGFR inhibitors as well as TKIs in general. These are completely reversible, asymptomatic, and consistent with our preclinical tox, which showed there was no evidence of hepatic cell necrosis. Very good data proved the concept of targeting FGFR3 as showing a substantially better tox profile. Great. OK, the last thing to round out, just understanding about this setting, could you talk about any progress or when we could hear next about how these patients are doing? There were a few patients who were just shy of that 30% tumor shrinkage mark. Is that something where those could mature and deepen over time, become additional responses to make this data set look even better? Yeah, we've actually really tried to round out the phase I portion of this study since disclosing that data. We had done some exploration with BID dosing. What we learned with BID dosing is it didn't improve the tolerability. Rather, actually, it felt like from what we were seeing, twice a day dosing might have increased a little bit on the diarrhea relative to the same amount given once a day. We quickly said QD is optimized for tolerability. We wanted to look at just a little bit higher doses. We prioritized looking at 100 mg and filling that up. That's data we've actually been collecting throughout the year, again, so that we could set ourselves up from a Project Optimus perspective to have a discussion with the FDA coming out of the phase I that we had two doses with distinct PK and activity and safety that could then be prioritized for a phase II. All that work has progressed very well throughout this year. The plan is to go ahead and wrap up that phase I as really our next step, talk to FDA about what a development plan would look like in the metastatic urothelial setting, and have that option to move forward. Mitchell, you and I were chatting a little bit before this call. From a prioritization perspective, this falls behind the other activities that we're doing. From the cost of capital to move this forward and the size of the population, given that FGFR3 positivity, it's quite a bit smaller in the metastatic setting. It's about 15% of patients versus that 70% in the IR NMIBC setting. Just the unmet needs that we could address by prioritizing and putting the cash near term in the intermediate risk setting, and then on the ACOM and other growth conditions, those are really important uses of the capital we have today. It's no surprise the biotech market hasn't gone gangbusters this past year. There's been a few years of challenges. We really consider the capital that we have quite precious. We are well capitalized for the next several years. At different points in time, we'll want to raise more money to go the full distance. We feel very confident that the data that will help us get there and that will really return the greatest investments is going to be what we're doing today in the intermediate risk NMIBC setting and the achondroplasia setting, and even in some of the other skeletal conditions that we might do as well. With that prioritization, it's an option. We're not really committing to timelines. Certainly, with improved cost of capital over time, I think it's a really important population to address. We're very focused right now with the two open phase IIs that we have. Great. Yeah, on that note, the other key indication for dabogratinib ACH, I want to move on to that and talk about the opportunity there. With the BH301 study for achondroplasia, you're starting at the 0.125 mg/kg- 0.5 mg/kg dose level with a sentinel safety cohort. How did you translate those pediatric exposures from the 90 mg and above dose level? How do those compare to infigratinib dose levels in pediatrics? Yeah, again, you're hitting the number one question investors love to explore. This is the number one question for us to get right as well. You want to get the dose right here and be successful. We feel confident we're in a really good zone with where we're testing. First off, really exciting day for us because we announced this morning our first child dosed in the BH301. I really just want to commend the community that's really gotten behind our approach with a lot of enthusiasm. That's the investigators, advocates, families that are really thrilled to have this FGFR3 selective option advancing, as are we. It's a humbling experience, truly, working with these families and with these kids. They have a ton of hope. We have a ton of hope. We want this to go incredibly successful. I think we're poised to do that now as we're getting our site set up. The engagement continues to improve. I think what we're able to articulate to these families that's so important is really the idea of what does FGFR3 selectivity do for you? How does that change the paradigm from what other treatment options that have come along? The condition is 99% driven by the same amino acid alteration, a glycine at the 388 position switching to an arginine, which then further stabilizes FGFR3 in the membrane and causes overactivity as that increased expression of FGFR3 interacts with FGF ligand. Because of FGFR3's primary role in chondrogenesis as a negative regulator, these children from the third trimester and then throughout their years of open growth plates are going to see a significantly reduced chondrogenesis impact that leads to shorter long bones. It also leads to these complications like foramen magnum stenosis, spinal stenosis, really scary sleep apnea, and airway obstruction challenges that happen with just these little infants as parents bring them home. Anything that you can do to improve, or if you will, reverse the effect of this FGFR3 overexpression has the promise of making a huge impact. We first saw that in our preclinical models where we put up really exceptional data with impact on foramen magnum, impact on histopathology, impact on long bone growth that really exceeded what others had seen across the board. What was most exciting for us is when we got into the clinic in the metastatic urothelial setting and we dosed through our 40 mg adult dose and we looked at the PK exposure, we were able to match that 40 mg dose exposure with the exposure that was so highly effective in our preclinical models. That's something that with a pan-FGFR inhibitor, you simply can't do. Infigratinib did test or BridgeBio did look at some higher doses in animal models. They saw better results. Those exposures translate to higher doses than they're actually using in their phase III because of the off-target effects of FGFR1 and FGFR2. We created this therapeutic index with the FGFR selective that allows us to explore the four doses that we're testing in BH301. The highest dose, that 0.5 mg per kg, is roughly equivalent to a 40 mg adult dose. The average adult was 80 kg in our MUC study. We are excited about the ability to get to these doses that were so effective in hitting all of the phenotype changes that you would want to hit in a preclinical model. It's not just that, though. There's really, really good data genetically, preclinically, and now clinically about the power of the FGFR3 target as it relates to growth and chondrogenesis. On the one side, we know that children and individuals with achondroplasia, on average, they're going to achieve, if you're a male, a height that may be 4 ft 3 in on average. That's versus a 5 ft 9 in for a typical population. We also have the other phenotype where there are conditions, one of which the acronym CATSHL is an FGFR3 single allele knockout. You haven't turned FGFR3 expression off completely. You've taken half the FGFR3 expression potentially off the table by eliminating that active allele. What you see there is the average height for a male is 6 ft 5 in. You get this 10% increase over a typical height with this condition. That's a lot of a very, very meaningful change just by getting to essentially what would be about half the expression of FGFR3 in terms of what we estimate. There's this clinical finding that the Memorial Sloan Kettering reported in typical children without a genetic FGFR3 condition but had somatic mutation in glioblastoma that was FGFR1 or FGFR3, and as a result, went on a pan-FGFR inhibitor like erdafitinib. They went on the full dose. A full dose of these drugs, the target is trying to get IC90, almost complete inhibition of FGFR3. What they saw there was quite shocking, actually. The children, while their growth plates were open, were growing upwards of 19 cm per year. The growth was so fast, they had some fractures and other challenges. What that highlights, though, is that this is a massive regulator of growth and that the dynamic range is extremely wide. A typical kid is going to grow 7.5 cm- 8 cm, maybe even 8.5 cm at certain times. To move that out to these high teens, have some complications, highlights that you don't want to be on the full FGFR3 suppression spectrum with any of these children. We do know that getting to somewhere around an IC50 on average is likely a relatively safe place to go. We see it in our preclinical models and just wild-type mice. We saw it in that achondroplasia mouse model. That's really helped us triangulate to where we wanted to be, the equivalent of a 40 mg adult dose. That was an incredibly well-tolerated dose that we put 10 patients on in our MUC study, which gave us immense confidence that as we go into children with the weight-based dosing and we move up these doses, we have a great shot at optimizing growth in the way that, again, not just about annualized height velocity, though that's a surrogate, but optimizing the potential to impact foramen magnum stenosis, spinal stenosis, back surgeries over time, and all of these other clinical complications that you want to hit. It really comes down to FGFR3 engagement and hitting it at the right dose. Strongly believe you can only get there where you want to be with an FGFR3 selective. BridgeBio with their pan-FGFR at the dose they're getting to, they're seeing similar efficacy as CMP. That efficacy from an annualized height velocity is only about half of where you really want to go with these children. We know there's plenty of room on the table. We just want to push that FGFR3 engagement to that right level with our dosing scheme in BH301 to optimize efficacy within that therapeutic window that we feel we've proven with the data that we have so far. Great. OK. Thinking about the efficacy bar, one of the questions we get from investors is infigratinib and Voxzogo are getting to the 6 cm per year. I know we've talked about it, but maybe it's helpful to just run through what level of AHV and cumulative adult height gain would establish true differentiation. Is there a limit? Is there a target? Could you help set the stage for what you're looking to achieve on AHV and height gain? You mentioned a couple of other things to differentiate. Could you just talk about what you're looking for to be a differentiated profile other than AHV and height gain? Yeah, you bet. BioMarin and Ascendis have done some really nice work recently highlighting kind of what the hope should be. In children that don't have an FGFR3-driven growth stature condition, CMP can have a significant impact because the break isn't on. They can push on the accelerator. They've moved kids that were at a baseline of under 4 cm to 8.5 cm per year and report really compelling safety and a really exciting outcome. A small group of children, but nonetheless, that's doubling the efficacy they're able to get to in achondroplasia. You're doing it safely in these situations. Ascendis, combined with growth hormone, saw 9.2 cm per year and report a safe outcome for these kids where they see that. That's an amazing target. It's quite a bit better than 6 cm. You're not going to get there, we strongly believe, without getting the right level of FGFR3 engagement. Again, it's not just about the AHV. It's really the promise of when you're able to reverse the effect of this alteration to bring expression activity down. The other health complications that children, families, and adults ultimately suffer, we have the potential with that right level of target engagement to meaningfully change those. It's been a struggle to date to show improvement with the height that they have demonstrated on some of these metrics. We're excited about that in particular, especially as we go into younger kids than this study, the opportunity to really start to see these meaningful changes on foramen magnum, cutting down on surgeries. I think it's going to be really exciting. Great. That's very helpful. Selectivity perhaps matters more in pediatrics than adults. With the selectivity profile, what pediatric-specific safety risks do you think that you're mitigating most? How are you designing the safety assessments to highlight differentiated? Yeah, I think our main focus, because we're doing dose selection, we want to make sure you want to be able to push growth. You don't want to push it too much and drive complications. I think that's one of our main assessments, just looking at what's the right and healthy level of growth that can be achieved during these initially 12-month windows, six-month windows. That's a very important safety parameter. Aside from that, it's really just recapitulating what we saw in adults around having a very tolerable profile by significantly reducing FGFR1, FGFR2, and FGFR4 activity. Confirming that while making sure that the level of growth that we're getting is optimized is, I think, the key safety bands that we're thinking about for this study. Great. For ACH, is there anything you can share on when we could expect an update in terms of data or the next path ahead for this program? Yeah, we put out some guidance this morning that by the second half of next year, we'll have some initial data. This will likely be coming out of our sentinel safety cohort. We anticipate we'll be on track to be able to start sharing some data. That kind of combines to make 2026 a really important year. It makes the second half of this year critical around execution as we continue to build the momentum. I think the sentinel safety data is going to tell us just an enormous amount and tell investors an enormous amount. We're going to have 12 children ultimately. By our estimation, the top three doses should have a level of target engagement that exceeds likely what we predict is exceeded by the pan-FGFR inhibitor infigratinib in their study. We will look for those children to outperform potentially on initially six months and then ultimately 12 months in terms of that initial surrogate AHV, which then I think can give us the belief and promise it's going to have a broader impact on all the other clinical sequelae and also read through as we add additional children in our cohort one and two onto the study. Great. OK. Moving on to manufacturing and formulation for dabogratinib, one of the dynamics I think is interesting, which would be helpful to highlight for investors, is the pricing and managing multiple different dose levels of dabogratinib across oncology and the pediatric microdose formulations, the tablets versus the caps. Could you just talk about what that would look like, just pricing and manufacturing, all of that kind of information? Yeah, I think it's important to highlight first and foremost that we have very different formulations and dosing schemes when we look at bladder cancer versus achondroplasia. Bladder cancer would be a solid oral tablet indicated, what we anticipate is likely a single dose regardless of weight. Whereas with children, especially because that weight is changing over time, we're going to have weight-based dosing. We've put this into a formulation of, call it this sort of sprinkle capsule, so it could be sprinkled over applesauce or yogurt and provided. Very different. Not only that, BioMarin has already done an excellent job of highlighting that payers across the world are willing to pay and actually willing to pay with what I know this isn't the right way to term it, but I'll call it subscription pricing. Whether you're getting a small amount of drug because you're three years old or a large amount of drug because you're 14 and your size is meaningfully different, it's really the same price month after month. That argument, and it's been done with other drugs, has already been made with payers in terms of paying for the outcome independent of the dose. There's a strong willingness to pay. BioMarin's done an incredible job now commercializing, nearly getting to $1 billion in sales with this, and doing so in a way that's largely ex-U.S., which is quite unique as well. There's a real strong precedent now set. There's really no risk of achondroplasia drug formulations being used in the adults because you just need so much drug. Actually, the price would be quite a bit bigger than if you just sort of repriced it around a tablet, which would be more standard pricing there. That allows us to eliminate this risk of kind of drugs being used across indications. We think it's a very low risk that someone would try and start crushing up tablets to sprinkle, not knowing the right level of dose for these children, especially in an environment where there's this willingness to pay. That gives us confidence we can brand and separate this very meaningfully from a manufacturing, formulation, branding perspective. Doug worked on a drug that did something very similar. Doug, do you want to speak to that example of what you guys did at Amgen with Prolia and Xgeva? Yeah, Xgeva and Prolia, two very different indications and two different in osteoporosis, Prolia and in bone metastases with Xgeva. They had different dosing and different schedules. As can be seen by the revenue from both of those indications, they managed to separate the two and achieve pretty optimal revenue in both indications. Very helpful. OK, great. Moving on to kind of the runway that you've spoken about through at least 2027, could you talk about what that covers in the big Tyra pipeline? Yeah, really, our cash runway, we anticipate getting meaningful phase II data across all of the indications we've talked about today in terms of intermediate risk NMIBC and achondroplasia. It allows us also to advance TYRA-430, which we haven't talked about, but another very exciting drug in hepatocellular carcinoma. Ultimately, with meaningful data, we'll obviously look for ways to extend that runway into phase III and ultimate commercialization. We feel very confident with the cash we have, we can deliver to investors very strong and compelling data packages phase II, highlighting what the recommended phase III dose should be and what the likely outcome and improvement we can achieve against the unmet needs in intermediate risk NMIBC and achondroplasia. Excellent. The last thing, would love to give you the floor to highlight anything we didn't talk about that you think is impactful for investors and the road ahead for the next 12- 18 months for Tyra. Thanks, Mitchell. We talked about a lot. I think what's least understood about our story is the dual opportunities are both amazingly attractive and can address these very large unmet needs. We have investors who are maybe really excited about what we're doing in achondroplasia. Some investors are really excited about what we're doing in intermediate risk NMIBC. Truly a rare opportunity where you've got what's now a clinically validated drug like dabogratinib with the safety efficacy profile that was seen in a very late line patient population that's hard to treat, with such compelling opportunities to change standard of care and make a really meaningful and lasting impact on lives in two very disparate but both compelling opportunities. It's a very unique setup for us. We're scientists. We built and made this drug out of, I think, a love for the science and understanding that this would be a potentially very valuable drug to make. It's great to sit where we are. We have a lot of work ahead of us just in terms of moving through phase IIs, IIIs, getting to commercialization. Yeah, such a great and compelling and exciting opportunity. From a competitive situation, I think we're pretty clear about our ability to outcompete and improve outcomes versus the pan-FGFRs. Lilly and the Loxo folks also had an FGFR3 selective. Data weren't as good as what we showed last fall. I think there isn't a plan, immediate plan that we've heard of moving into these bigger and exciting opportunities. One of the things that also happened this year for us is just creating some additional daylight between us and competition that will ultimately come. It's a really great setup. There's more to come from what we're ultimately going to build out of the pipeline that we're excited about as well. Excellent. Todd and Doug, thank you both very much for joining us today. I want to send a special thank you to all the investors who dialed in as well. Really appreciate it. Thanks, Mitchell. Thank you so much.