Tyra Bioscience Aktie

Welcome to Tyra Biosciences webcast and conference call on the initial SURF302 results. Today's conference is being recorded. At this time, I would like to turn the call over to Todd Harris. Please go ahead.

Thank you, operator, and good morning, everyone, and thank you for joining us. I'm Todd Harris, CEO at Tyra Biosciences, and we are thrilled to be sharing with you the results that we're seeing in our SURF302 study, evaluating oral dabogratinib in patients with intermediate risk NMIBC.

I'd like to begin by thanking the patients, their families who participated in the study, our investigators, study coordinators, employees and our shareholders. None of this would be possible without you. Before we begin, I'd like to remind everyone that during today's presentation, we will be making forward-looking statements, including statements about our future clinical plans, data and strategy and potential therapeutic benefits of dabogratinib.

These statements are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to the slide and our SEC filings for cautionary language and a discussion of these risks. We undertake no obligation to update these forward-looking statements, except as required by law.

I'm pleased to be joined by our Chief Medical Officer, Doug Warner; also Dr. Mark Silva from Greater Boston Urology, a community urologist out of Boston, who's actually participated in both of our SURF302 and SURF303 studies. He is here to share his perspective on both the data and the impact of oral dabogratinib for his potential patients in practice. I'll share some market insights upfront. Doug is going to be walking through the data, and we have other members of our team, including Alan as well.

We are excited to share today that we believe we have a drug with dabogratinib. At the 60-milligram dose, we are seeing the safety for chronic dosing, the clinical efficacy and the convenience of an oral therapy that could truly shift the paradigm of treatment in this setting of intermediate risk NMIBC. I've talked a lot about the patient journey in the past. Patients with intermediate risk NMIBC suffer from multiple procedures, surgeries and over instrumentation. It is the key unmet need.

And for the first time with the data we're sharing today, we can envision a future where the procedural burden could be replaced with the convenience of a simple oral drug at home. Now this population, of which there are about 50,000 new patients seeking treatment every year, 70% of these patients actually opt out or forgo an effective treatment that's been proven to reduce recurrence.

That's a treatment involving induction and maintenance chemo, and it's in the guidelines. Why are they opting out of or foregoing this effective treatment? It's because this is a disease that's not likely to progress, but is highly recurrent. And facing the choice between multiple catheterizations and procedures that would be required to maintain a disease-free status, most patients are simply waiting to recur.

And when they do recur undergoing a single operative procedure instead of the multiple catheterizations. When we look specifically at the largest population, the FGFR3-positive population, it's clear this is the population with the highest unmet need. Really meaningful data from Dr. Meeks at AUA this year highlighted that FGFR3-positive patients have a median recurrence-free survival of only 16 months versus the broader population that's not FGFR3 having a median RFS of 40 months.

It is clear that this is a signal that is causing multiple and frequent recurrences. And by suppressing this signal, we have the opportunity to change the patient journey and bend the curve towards a longer disease-free survival. And the evidence is already there. We've seen with intravesical and oral pan-FGFR inhibition that as long as FGFR3 is being suppressed, we can see 100% durability.

But in all of these examples, when that FGFR3 suppression signal goes away, patients come off treatment, we see a high rate of recurrence that starts to happen right away. 3 of 4 evaluated patients in that THOR-2 Phase2 study actually came off of therapy and recurred within 3 months. 4 of 6 patients who had discontinued treatment had recurred within a year.

When we think about how can we maintain treatment and the broader pipeline, all of the approaches that are moving into Phase 3 adjuvant studies require multiple urethral violations to be effective. This is continuing this paradigm where patients today are voting with their feet not to undergo treatment. With an oral drug in dabogratinib, we have the potential for chronic suppression, chronic dosing with the safety signal and the efficacy signal we're talking about today that it could actually change the paradigm for these patients in maintaining a response and avoiding recurrence.

Now the study that we designed to demonstrate this is our SURF302 study, and it's the data we'll be sharing today. It's important to highlight that this is a marker lesion study. What does that mean? That means that at least one marker was left behind in the tumor and drug was given to identify at which dose can we see that marker lesion shrink or disappear. We actually, with the design of this study, have 2 studies in 1. We allowed both patients with a single marker lesion, which is a really high predictor of adjuvant success. And this was the criteria that the one predecessor study to the criteria that they use. But we also use -- we also looked at patients with multiple marker lesions, which could give an initial indication of dabogratinib use in an ablative setting. We tested 2 doses, 50 and 60 milligrams. Both of these doses were chosen as potential doses to cover our IC50, which has an AUC of 2,500 nanogram times hour per ml. And we'll highlight in the data today why that's important and why we think that we're seeing a great dose response between 50 and 60 milligrams.

And then finally, the endpoints -- the primary endpoint was CR at 3 months. But because of the importance of the adjuvant signal when a lesion is shrinking greater than 50% and no new lesions are appearing, we also look at best overall response as a clear indicator that there's enough drug on board with a particular dose to shrink the tumor and to potentially have an effect in an adjuvant setting.

So what are we seeing? Well, initial data shows that where we look -- when we look at the study with single marker lesions, we have 100% ORR at our 60-milligram dose. Recall, this is an ablative signal-seeking study. So when we look at the single marker lesions, and this was the way the THOR-2 study was ran -- we see a 100% ORR and we see a best overall response of 75% CR.

This is exactly the benchmark we were hoping to see THOR-2 like efficacy, but with a much improved tolerability, which as Doug walks through the data today, you'll see. At 60 milligrams, we're seeing the safety signals that could support chronic dosing potential. And all this comes together to highlight a very high probability of success in an adjuvant Phase 3. So 60 milligrams is the go-forward dose we are planning for an adjuvant Phase 3 versus a placebo. What the data also show here, and we'll highlight this that with multiple marker lesions, the responses aren't as strong.

And so when we think about the potential of using dabogratinib in an ablative setting, it's clear that potential more drug on board could be helpful for ablation. And so we will be studying a 70 mg dose expansion in SURF302 prior to considering whether we further expand this study towards lesions of all sizes in an ablative setting.

But to be clear, the biggest opportunity we're pursuing where 85% of the market, we believe is, is in the adjuvant setting, and that is the Phase 3 dose selection that we're moving forward with and talking about today at 60 milligrams. So with that, let me hand it over to Doug to get into the study details. Doug?

Thank you, Todd. The SURF302 enrolled a highly recurrent untreated population. This is very consistent with the overall patient population in low-grade IR NMIBC. This is an elderly group of patients, the vast majority of which had recurrent disease and had prior TURBTs up to 10.

Interestingly enough, as Todd pointed out, this patient population, the majority, did not receive intravesical chemotherapy. This patient population had a high tumor burden with over 1/3 of patients had greater than 1 marker lesion at baseline. In addition, total aggregate tumor size was 10 millimeters in 1/4 of the patients.

Overall, when we look at the safety data, dabogratinib showed favorable safety and tolerability that support chronic dosing in this indication. Adverse events were manageable. There was no clinically significant hyperphosphatemia, nail toxicity or ocular toxicity. These are common toxicities that affect quality of life that are associated with pan-FGFR inhibitors. Importantly, as well, there's a low frequency of transaminase increases.

When we look at dose modifications, first at the 60-milligram dose, there were no dose discontinuations or reductions. There are only 2 AE-related dose interruptions that are related to dabogratinib. At the 50-milligram dose, we had 1 dose discontinuation and 1 dose interruption, and I'll go into those 2 cases in a little more detail in a second here.

We look at the overall safety data, the vast majority of treatment-emergent adverse events were mild and moderate, so low grade. At the 60-milligram dose, we had 3 Grade 3 UTIs. These were all unrelated events. At the 50-milligram dose, we had 2 Grade 3 events. One of these events was a Grade 3 rash, which resolved with dose interruption and low-dose steroids. The other Grade 3 event occurred in a patient who had normal LFTs and then was started on Macrobid for a UTI, a known liver toxic drug and subsequently developed Grade 3 AST/ALT elevation and was discontinued from study drug.

Looking at the treatment-emergent adverse events of greater than 10%. The level of fatigue is consistent with what is seen in the placebo arm of trials in this patient population. We've not seen a fatigue signal in the data to date with dabogratinib. Dry eye, there are Grade 1 dry eye events. Grade 1 dry eye is an asymptomatic event. So the question is, how did we pick up these events? It's because since pan-FGFR inhibitors are associated with ocular toxicity, regulators asked us to perform comprehensive eye exams regularly. So we had these exams every 3 months, and these were asymptomatic findings that were picked up on these exams.

I want to go into a little more detail on the episodes of diarrhea in a moment. It's important to point out also that AST/ALT elevation did not rise above 10%. GI events overall were limited and transient. Here, we're seeing all diarrhea treatment-emergent adverse events set against in the light gray, the time on treatment in both dose cohorts. So the diarrhea AEs are superimposed on the time on treatment. There were no dose reductions or interruptions from treatment-related diarrhea. And as you can see by the swimmer plot, almost all of these cases were transient, brief, self-contained episodes that resolved.

A couple of these cases I want to go into a little more detail on. First, at 50 milligrams, the patient at the top with long-standing intermittent diarrhea. This is a patient who had over a 10-year history of diverticulosis and diarrhea prior to study entry and also a 10-year history of intermittent use of Imodium. Another case I want to point out is that the 60-milligram dose, the Grade 2 diarrhea, this was a diarrhea event considered unrelated to study drug and related to GLP-1 usage.

Now, turning to the efficacy data. 60 milligrams demonstrated strong clinical activity, and there was a clear dose response between 50 and 60 milligrams. The overall response rate at 60 milligrams was 79% and the best overall CR rate was 64%. There was 1 patient who had a PR at the 3-month assessment that converted to CR at the 6-month assessment. At 50 milligrams, you can see once again a clear dose response with a CR rate of 33%.

I want to point out as well that all patients who had 3-month CRs maintained that CR at the 6-month assessment time point. So we're going to look into these data in a little more detail here with swimmer plots clearly showing evidence of response maintenance and maturation. Here, we're seeing a swimmer plot in order of patient enrollment on the study and also looking at baseline pre-resection number of lesions and the number of marker lesions post resection.

Zeroing in on the 60-milligram dose, you can see we had 2 patients with CRs at the 3-month time point that were maintained at the 6-month cystoscopy assessment. In addition, we had that 1 patient who had a PR at 3 months who converted to a CR at the 6-month assessment. There was another patient who had a PR at 3 months. Unfortunately, this patient who had a history of kidney stones prior to study entry had multiple hospitalizations due to kidney stones and complicated UTIs. These were not related to study drug, and that patient had to be discontinued from the study due to the lack of compliance with dabogratinib.

I want to move on and discuss some initial data from our SURF303 study evaluating the use in upper tract low-grade urothelial cancer. This is a cancer, a cell type that is the same as that in low-grade intermediate risk NMIBC, but due to its location, the ureters and kidney, presents particular problems of management, and unfortunately, sometimes results in kidney removal.

So this is our patient who was first -- our first enrolled patient on the trial, was enrolled at the 60-milligram dose. Patient has a substantial number of comorbidities, including Type 2 diabetes, coronary artery disease, multiple ocular conditions. And the patient had multiple prior treatments as well as JELMYTO with a renal pelvis lesion of 5 millimeters at the first assessment. At 3 months, patient had a complete response and had no on-study AEs and no significant changes in lab values from baseline. So this adds to our understanding, showing the tolerability and efficacy associated with the 60-milligram dose.

Thanks, Doug. I'd now like to talk about how we can use the data we're seeing today for our dose selection in Phase III and a Phase III adjuvant study. First off, we looked at a major driver of efficacy being AUC exposure. We had identified a target of an IC50 of 2,500 as being a key target we wanted to cover.

And when we look at the 26 patients across all the doses, 50 and 60 milligrams, and those that cover that IC50 and those that don't, we see a clear distinction in efficacy, 86% best overall response and a 71% CR rate for those that hit that AUC coverage of 2,500 versus a CR rate of 25% for those that don't. This allows us now to model using the 172 patients who've had dabogratinib and had PK measured an extensive population PK model, highlighting that the doses we've chosen are in the steep part of the dose response curve. And once we get to the 60 milligrams, the vast majority of patients are hitting that AUC target and expected as we're seeing to potentially be in a response.

There's a second driver that's also very important, and we touched on this in the beginning. Clinical activity clearly improved in patients with a single marker lesion. You can see here on the left, 50 and 60-milligram dose pooled, but then broken down for those patients who had the THOR-2-like criteria of only a single marker lesion. And we're seeing excellent activity, best overall response of 94%, a CR rate of 56%.

For those patients with multiple marker lesions, we see a degradation of that at only a 40% ORR. It's important to point out for those patients that are responding, those are the patients that have some of the highest AUC. They're all covering that 2,500 nanograms times hour per mL. And it's also important to point out, of those patients that did not respond, 6 of them -- 6 of the 7 were these multiple marker lesion patients.

We now, with this information, really have a clear answer, one that we didn't know before, which was if we were to run a study like THOR-2, it's just a single marker lesion might the data have looked differently. And we can apply that lens here and see clearly that indeed, we see a better response at the 60-milligram dose, 100% ORR, our CR rate maturing to 75%, really hitting that benchmark we wanted to see and giving us a high degree of confidence that 60 milligram should be the go-forward dose in this adjuvant setting.

Adding to that confidence is our modeling of the actual end mark -- actual endpoint that's measured in an adjuvant Phase III. This is for us a disease-free survival curve. And we're leveraging the data from Dr. Meeks in that 16 months PFS -- median PFS to showcase that. On placebo, the expectation is the population, 64% of patients would recur and 36% would remain tumor-free.

We can now apply the activity we're seeing to that 64% of the population that's at risk and taking certain assumptions of the CR rate and durability start to project some scenarios. In the most conservative scenario, if we were to pool all doses, 26 patients, the CR rate we're seeing across 50 and 60 milligrams is 50%. And if we were to take a very conservative duration applied to that 60%, why is that conservative? Remember, 3 studies now, including ours, have demonstrated that as long as FGFR3 suppression is maintained after a CR, the durability is 100%. Now we haven't measured all patients out to 24 months, but it's a clear signal that durability should be good. Even in this very conservative scenario, we would land at a DFS of 55% with an implied hazard ratio of 0.6. That would be a successful Phase III study.

Additionally, we can look at the scenarios, the 60 mg dose, applying that CR rate of 64%, a durability of 80%, applying a PR rate of 14% and a discounted durability, we would get to a 72% DFS. And now, let's take the THOR-2-like design, which would be the single marker lesion patients at 60 milligrams, 81% projected DFS. Taken together, these data suggest across the board, we have a high probability of success and potential best-in-class efficacy that we could deliver in these patients with the data that we're seeing today at 60 milligrams.

I'd like to now just spend a moment talking about what is the potential for these data to transform the standard of care. Recall, the market today is segmented in 2 important ways. For those patients who are seeking treatment with repeat catheterizations and instillations, we have an opportunity to win on efficacy and convenience with oral dabogratinib. They've got instrumentation fatigue and potentially replacing this intravesical approach with an oral could be a game changer. And we see recent evidence of a case study that's highlighted just how this is happening today in the urologist office.

ORGOVYX is replacing a 35-year entrenched player of generic Lupron. That is occurring because, one, the mode of administration is excellent, that ORGOVYX and the commercial team have aligned the practice economics so that community urologists through in-office dispense contracting and limited distribution can participate in the economics with an oral just like they do with Part B. It's also streamlined the operations significantly for their offices as well. ORGOVYX is doing over $1 billion and is projected to grow 80% next year. This is a great commercial success, and it highlights how we might think about the oral commercialization for dabogratinib in this setting.

But it's not just the small population that's currently seeking treatment. There is this very large population, 70%, that's waiting to recur. For this population, we can offer an oral to reduce recurrence and surgery, potentially even reduce the 3-month cystoscopy burden. Taken together, this is a really large opportunity, and it's highlighted by the patient surveys we've conducted, shown here.

The #1 appeal that patients highlight about the value of an oral drug is greater privacy. Patients are looking to take control of their disease. They're sick of having to drive to the office, have family members drive them to the office. They're sick of the discomfort associated with catheterization, the travel time, the time away from work. Oral dabogratinib has the potential to really resolve some of these key issues.

And when we've asked patients about the value proposition of an oral, even if they still needed 3-month checkups with cystoscopies, 77% agree the value proposition is still very strong and very large. Now, we've also surveyed urologists, and the overwhelming feedback has come back. Urologists would recommend patients try an oral before a pretzel and other catheterization techniques. Why? Because they've actually highlighted that the biggest unmet need for their patients is the repeat catheterizations and the invasive experience.

Even more so than the need for a durable response and reduced recurrence, it's seeking to reduce this over-instrumentation paradigm. And oral dabogratinib has that potential to do just that. Taken together, this is a very large opportunity. It's a $5 billion-plus market. We have with the safety, potential chronic dosing, the efficacy and the convenience of an oral, the opportunity to be a clear first-line choice for all of these patients.

And so now, I'd like to hand it over to Dr. Mark Silva to share his perspective as an investigator and as a community urologist on the data that we've shared today. Dr. Silva?

Thank you, Todd, and thank you for inviting me to join you today. I am a practicing urologist. I'm a community-based urologist and investigator in both the SURF302 intermediate-risk NMIBC study as well as the SURF303 low-grade UTUC study. Intermediate-risk NMIBC is one of the most common disease we treat, but it's also one of the most frustrating. It's a recurrent disease, but it's not a progressive disease. Patients often live with recurrent disease for years. They undergo repeat cystoscopies, surgeries under anesthesia, intravesical treatments, repeated catheterizations and bladder instillations. They come to the office once a week for 6 weeks. Their urologist is one of their best friends, and they know all the staff here for those reasons.

In my experience, the biggest barrier isn't the patients don't want to reduce their risk of recurrence. They just don't want to go through the treatment process. They don't want to go through the journey that's currently available. That's why I find both these studies as well as the data very encouraging when it comes to Tyra and the dabogratinib. Oral dabo has demonstrated meaningfully -- meaningful clinical activity together with favorable safety profile and just a very easy mode of administration every week, every day.

I have conversations with patients who are hesitant to undergo repeated intravesical therapy. It's a hard sell for patients to come in for similar treatments that they get for high-risk disease. And they end up choosing surveillance instead of treatment because the options are invasive and difficult to live with. They have to leave work. They have to miss school. They have to miss their life, just they decide to live life by essentially waiting to recur instead of going for treatments.

When it comes to oral dabo, if we had this effective oral well-tolerated treatment, it would be changing the conversation that we have with patients pretty significantly. When it comes to an effective oral option, this could empower patients, giving them more control over their disease and treatment. As you discussed beforehand, it's the privacy. You could take a medication at home with your regular statin or your aspirin instead of coming in to have a catheter placed and exposing yourself in the office. It's just a difficult life to kind of go through.

So I think all of this, the data, the ease of administration is all meaningful win for patients, providers and our health care system. From a clinical trial perspective, I also find the planned Phase III strategy very compelling. It's going to be very exciting, and we've already gotten approved to be at site. So we're very excited for that. An adjuvant study evaluating a well-tolerated oral therapy in this patient population addresses a very real unmet need, as we've discussed. And I believe it will resonate with both physicians and patients. It's exactly the kind of study I'd be excited to offer in my practice, and it's going to become part of our practice, not just from my solitary practice, but as in urology practice across the board.

When it comes to FGFR inhibition, it's going to be very exciting to see it both as bladder as well as upper tract. And although a more rare disease, it is something that is going to be very exciting to not have to say you're going to go for a large robotic surgery to take your kidney out versus taking, again, an oral medication in the privacy of your own home.

So obviously, additional follow-up with larger data sets is going to be on the horizon. But as someone who treats these patients every day, I think that oral dabo is going to be very revolutionary in the low-grade intermediate risk NMIBC, and it's going to become a very big part of our practice going forward.

So I'm going to turn it back over to Todd at this point.

Thank you, Dr. Silva. I appreciate those very helpful perspectives. Just to close up here, I want to talk about the next steps. The clinical momentum continues as we've seen today on our dabo 3x3 strategy. We now have our first clinical proof of concept, a selected dose of 60 milligrams that we're going to be potentially moving forward in an adjuvant Phase III. We're going to engage FDA on these results and that Phase III design as a next step and prepare to initiate a study next year.

Additionally, we now are really excited to see this first patient respond in UTUC at a 60-milligram dose achieving a CR. It's great demonstration of initial activity. There's more patients, and multiple doses here are 60 and 80-milligram doses to evaluate in this ablative setting. So you can expect that we'll have initial results across these doses next year in 2027.

And finally, I'm excited to announce as well that we've now cleared our dose level 5 with no safety signals. That allows us or sets us up that in Q1 of 2027, we'll have the first 25 patients across 5 different dose levels in sentinel participants with 6 months AHV to report out.

So with that, I'd like to hand it back to the operator, and we'll take questions.

[Operator Instructions] Our first question comes from Tyler Van Buren with TD Cowen.

Maybe 1 for Todd and 1 for Dr. Silva. Todd, it's clear that single marker lesion patients are closer to the adjuvant patients with 0 lesions that will be treated in the Phase III. But can you discuss the rationale as to why a marker lesion study of this design was employed in Phase II? And also, what the THOR-2 experience tells us about how the CR rate should trend over time?

And then, Dr. Silva, I know you touched on some of this already, but can you elaborate on what enrollment was like in the SURF302 study based on your experience? And what you anticipate Phase III enrollment will look like so we can get a better sense of patient demand versus alternative therapies?

Thanks, Tyler. Let me tackle the first question. A marker lesion study is a very unique study. It gives you the opportunity in a very short amount of time to understand whether you have enough drug on board for an adjuvant setting rather than waiting 24 months for patients to recur. By leaving a small marked lesion and seeing it disappear and shrink, you have an opinion to know that your dose will essentially be effective for the adjuvant setting.

Now, there's 5 programs that are moving into late-stage development. 3 of them move forward without even running a Phase II. It's really only us and J&J that have employed these marker lesion type studies to move forward. THOR-2 was designed with a single marker lesion, and you see the efficacy really benchmark that we've talked about. We designed a study that had both single marker lesion and multiple marker lesion and allows us to get a broader understanding of the drug at the dose that we're testing.

For that single marker lesion comparison, we're seeing the THOR-2-like efficacy that we wanted to see. And investors will recall, we said for months now that if we could hit THOR-2-like efficacy with a superior safety profile that we're sharing today, that would be lights out data. It would be lights out data because we have a dose to move forward with an oral and it's something that no one has been able to do before.

THOR-2 was shut down as a study because of the tolerability, and it moved to the pretzel, the TAR-210. Really, that's the only other study now that's run a Phase II and is now moving into Phase III. All of this combines to allow us to now project a high likelihood of success when we model the actual endpoint in Phase III, which is a disease-free survival.

When we look at our 60-milligram dose, really in all of these scenarios, we can now move forward into a Phase III with a very high degree of confidence given the data set we have. Now of course, we need to talk to FDA about that, which is the immediate next step. But this really puts us in the best position with the breadth of data that we now have pointing to both the dose, the placebo effect and the likelihood of success in Phase III.

So with that, let me hand it over to Mark to answer the second part of the question. Maybe just 1 more thing before I do that, though. One question we get a lot, and it's really important, when you think about the THOR-2 efficacy, a lot of investors sort of expected an 89% CR rate out of the gate. And we spent a lot of time over the last few months educating folks that the actual 3-month CR in THOR-2 was 72%, but then, it matured over time to 89%. That's exactly what we're now seeing in our data as well. CRs persist, and PRs convert to CRs. That's really important because the best overall response today we're seeing today is not the best overall response that we'll see tomorrow as we watch PRs. And if they mature, convert to CRs, the data actually mature towards the ORR. So that's just really important distinction.

We can, in this initial time point, see that we've got a dose, but of course, over time, we'll see the durability and the maturation, but we can make a go-forward decision, which is what this study was designed for.

So yes, let me hand it over to Dr. Silva now on the questions you had about running the study.

This is Mark Silva here. So for -- regarding the enrollment in the study, always enrollment in clinical trials is usually kind of a discussion and in-depth with the patients learning about the protocol and learning about how to enroll and what enrollment being on study means, the idea of taking an experimental drug, and then, all the visits that kind of come up on with that because there are a lot of visits.

I've had almost the exact opposite situation with enrollment in the studies. These patients, again, this is the experience, we have to -- I'm trying to push the experience of these patients. They go for surgery. They come in for treatment, so they're getting a catheter in the bladder. They're getting medication put in the bladder. They're holding it for an hour. They're going home, they're missing work. They're coming in for invasive procedures.

These patients have had resections, have had biopsies, had fulgurations. They've had their urethra violated. They can have strictures. They can have contractures. They can have lower urinary tract symptoms. All of these symptoms and all of this discomfort leads patients to say, yes. When I say there's an oral medication that we can use, I barely get that sentence, and they're like, "Sure, I'm in," because, again, this is the patient experience. I haven't discussed with them the oncologic data or the reason or the reason for the studied FGFR mutation, the patient is in.

And when they hear that they are either an FGFR mutation positive or negative, they're excited to go on study. The ones that -- and they're rare, again, about 5% of patients, 5% to 10% of patients are FGFR negative, they come back, and they're upset. Why? Because they have to go for -- sorry, they have to go for a procedure to resect the tumor. So enrollment in this study has been exceedingly easy because the option -- the other options are just so uncomfortable or just such a tedious task. So it's really been an ease of enrollment onto the study and that discussion with the patient and their experience is really kind of driving that ease of enrollment.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the update. Wondering just as the data mature, when should we expect to see longer follow-up data from this cohort of patients? What could the cadence of updates look like going forward? And how do you expect the durability to shape up compared to intravesical treatments?

Yes. Thanks, Maury. Really, the most important next step for us is to take this data set to FDA and align on our Phase III protocol design. So that's really the next year opportunity when we're moving into Phase III to highlight that alignment and that ultimate design.

As we go, though, this study is designed to have treatments -- or to have patients on treatment out to 24 months. We're going to be enrolling 30 patients at the 60-milligram dose. You can see that we already have for safety 22 enrolled, so we're nearly there. And we'll be able to follow those patients out for that entire 24 months. So as we move forward with alignment with FDA on the Phase III protocol, there will be an opportunity at that point in time prior to launching the Phase III to talk about maturation data. And as we go even further, following these patients out to 24 months.

Got it. That's helpful. And maybe a question for Dr. Silva from the safety signals observed in this population, which one do you think needs to be most closely monitored in practice? And maybe for the company, for the 36% fatigue you're reporting in the 60 mg cohort, can you elaborate on whether that's chronic or transient?

So far, the patients who have been on study with me, I haven't had many adverse events or any issues. I think when you asked about the fatigue, it's a minimal amount, and it is transient. It's usually like the first couple of days that they start the medication and then has been -- done for a couple of months, and they're saying it might have been that, "I had a lot of stuff going on, I was traveling to and from". So it's not any sort of fatigue that is disease or medication changing.

Yes. And just in terms of the fatigue we're seeing on the study in terms of the data, it's a mixed picture versus transient versus chronic. But once again, it's an open-label study. And in placebo studies in these type of populations, you're seeing these rates of fatigue. So in an open-label study, this kind of data is difficult. We haven't seen this signal with the program to date.

Our next question comes from Chris Raymond with Raymond James.

And maybe a question for management and also one for Dr. Silva. So maybe first, Todd, before the study was published at AUA this year, I think the thinking was that a placebo disease recurrence rate at 24 months would be about 60%. This new data obviously refines it to just FGFR3 positive patients. But just reading the study, it looks like they measure low-grade and intermediate-risk patients. Maybe just sort of walk us through the math from the study that gets us to that 36% at 24 months. And any sort of commentary as to how you feel this will hold up with subsequent studies when those are done looking at just TURBT alone?

And then, I have a follow-up for Dr. Silva.

Yes. Thanks, Chris. It's a great question. And I think there are a few brand-new pieces of information that we shared today in addition to our data, and this was one of them that we're now talking more about. This was a relatively large study. It's actually the largest, most sort of controlled prospective data set that we have now around the precise population we plan to treat in Phase III, low-grade FGFR3 positive intermediate-risk NMIBC. So even when we look at maybe some of the other Phase III datasets that would read out, for example, CG Oncology's observation arm, it's not going to be as pure of a signal as this is for us in anticipating what we might see in a placebo.

So now some of these patients could have gone on intravesical maintenance chemo, but as you know, that would have been a relatively small proportion. And that would only degrade the data further if intravesical chemo and maintenance had an effect. So you translate this 16 months -- this median 16-month recurrence-free survival in a simple algorithmic exponential algorithm, and we have that highlighted on our Slide 20. That's what essentially gets you to the 36% at 24 months. It's the typical model, the exponential model you would apply in the Kaplan-Meier curves with that 16-month RFS is how we get there.

And then maybe -- and then a follow-up for Dr. Silva. I guess, back also to that AUA study from May, it's pretty striking how poorly FGFR3-positive patients do from this data. Did you have an inkling in your practice of this difference before that data?

So across the board, the study that you're mentioning specifically was testing FGFR-positive people. FGFR positivity is not actually routinely checked across our practice, and I don't actually know too many specific vendors that do FGFR testing specifically. That is becoming more popular. FoundationOne has now an FGFR mutation test, and we are actually working to bring it in-house into our practice across not just our practice, but kind of our larger consortium because this is data that we do want to know.

If the data shows that FGFR-positive people have worse recurrences or higher risk of recurrence, so we want to know about these people earlier. And I think that is kind of good data for the Tyra medications out there because we do want to escalate care when it's needed. So if we test more for FGFR mutations, then we would be able to potentially get more patients on the medication.

Our next question comes from Brad Canino with Guggenheim Securities.

I'm really trying to understand this interplay between the 3-month CR and the 2-year adjuvant study. And I'm wondering how much of the Phase III DFS effect size is expected to be captured in year 2 of the therapy, where presumably only a safe oral drug can be given for those extra months of 13 to 24. And then, depending on your answer, I'd be very curious about how much follow-up from the full 30 patient 60 mg cohort you can show next year to demonstrate that the CRs and the tolerability are maintained beyond year 1?

Yes. Thanks and great questions. We heard repeatedly from physicians, this is all about tolerability and durability if you're going to think about the maintenance of -- or a chronic dosing regimen with an oral. And you've highlighted something really important, which is our plan is to treat all the way through 24 months to have a sufficiently tolerable chronically dosed oral.

The direct competitor comparison in the FGFR3 positive space is erdafitinib and the pretzel, the TAR-210. Their Phase II and now their Phase III had treatment for 1 year, and then, the patients come off treatment. And we're already seeing, as I highlighted in the initial Phase II data in THOR-2, that if you take patients off of FGFR3 suppression, the recurrence rate appears to come right back online quite quickly.

So if you combine Meeks data now, and you look at that high rate of recurrence kicking off in, call it, month 13 to 24 if you're not maintaining the suppression, you can imagine how an intervention that is only designed because of the burden of instillation to work for 12 months could be very quickly in the pursuing 12 months. And oral has this opportunity to treat across chronically for that 24 months and then ultimately win on efficacy when you start to look at the long-term outcomes, which is what patients care about most.

And then on the data update potential in terms of follow-up for the next disclosure?

Yes. So of course, as I mentioned, we -- this is a study that will follow these patients out to 24 months. There will be plenty of opportunities to provide data updates, maturity. Again, additional and on the efficacy evaluable, it will go up to 30 and then time lines all the way up to 24 months. So expect from us, of course, next year, certainly around a Phase III start after alignment with FDA, an opportunity there, but you could imagine sort of every year this goes on, we'll have an ability to really speak to the metrics around durability that we're seeing, conversions of PRs to CRs, CRs maintaining. All of that can then feed back into our model to predict Phase III success. And we'll be able to do that in real time while we're kicking off the study and enrolling patients.

Yes. And then beyond bladder, obviously, you have a very safe dose that covers IC50. What do you think that means for development of achondroplasia? That's it for me.

Yes. Great question. And obviously, we're really pleased that we've now cleared dose level 5. And I'd say, us coming right in line with the target engagement we hoped for at these doses just gives us confidence that our translational models are working, that we can predict the right types of doses to be testing. And we feel confident that the 5 doses we have where the safety has been excellent so far in the kids has the potential to really hit that endpoint we're looking for, which is improved initial annualized height velocity, which could ultimately translate to meaningful clinical outcomes for these kids.

Our next question comes from Sami Corwin with William Blair.

I have one for Dr. Silva and one for Todd. Dr. Silva, I guess, do you agree with the interpretation of the marker lesion data? And would you have expected patients with a higher number of marker lesions to not respond as well?

And then kind of continuing off that last question, Todd, how are you kind of thinking about the read-through to achondroplasia here? And keeping in mind that achondroplasia patients don't have marker lesions, would you expect the exposure of dabo to translate in the same way to achondroplasia? Or would you think about exploring additional dose levels given you are seeing a tolerable safety so far at dose level in achondroplasia?

So for the multifocal...

Mark, maybe you could start.

Yes. Regarding multifocal disease, I mean, when it comes to bladder cancer, multifocality definitely always increases the amount of complexity when it comes to the patient. You have low-grade disease. If it's a small and solitary lesion, you're a low-risk patient. But if you have 2 lesions, then you're automatically an intermediate risk patient. So of course, multifocality is going to add to the disease complexity and will make it more difficult for a certain amount of medication to manage that bladder.

When it comes to the length of disease and the dosage needed, I think it's appropriate. I think that the data is kind of similar to what data from other disease states and what TAR-210 shows for non-muscle invasive bladder cancer in a similar state. I think it's just that the multifocality adds to the difficulty of the disease management.

Yes. Thanks, Mark. And getting into achondroplasia, the key dose levels, 1 through 5 that we have, are really, again, hitting target exposures that translationally, we think will essentially improve outcomes and efficacy beyond what the other treatments have been able to show in achondroplasia.

The key thing that we are looking to avoid now that we see such excellent safety across so many studies, we don't have a significant concern around safety from pan-FGFR activity with this agent. We have a very strong therapeutic index. So now what we're indexing towards is making sure that we're safe with our FGFR3 suppression. We don't want to get into a situation of suppressing FGFR3 so much that you can move to bone overgrowth. This is a toxicity that is seen in our animal models. And so we want to make sure that the exposure isn't pushing beyond an IC50, certainly not pushing to the sort of IC90 suppression.

And we remain confident with all of the data that we're seeing that within the 5 dose levels, we should still be safe as it relates to drug. And if we were to see anything, obviously, we would manage that. But we're not really concerned with safety signals from what we've seen outside of overgrowth, and we think that the dose levels we've chosen should track us towards where we want to be on improving efficacy without pushing too far.

Our next question comes from Mazahir Alimohamed with OpCo.

I think just one for you, Todd, and then, one for the physician as well. But first, as we think about the PFS or the PRs turning into complete responses, I guess with the patients that haven't reached the 3-month assessment, when those read out, are they weighted toward either dose or towards single versus multiple lesions? And of the 3-month PRs at 60 milligrams, how many have reached 6-month assessment?

And then, as you think about clinically, how are these patients -- this kind of something I was just trying to wrap my head around. So assuming they get on the oral pill, how will routine cystoscopy still remain for these patients? Would this allow these patients to completely -- basically, get off cystoscopy completely? Or will they still require like a yearly surveillance cystoscopy in the background?

Yes. Thanks for the question. I think that we have that detailed swimmer's plot in the presentation that we shared today. So that shows you exactly where we're at today with the patients that have at least been on drug for 3 months. As you'll see from our safety data set, there are additional patients evaluable for safety that hasn't quite yet got to 3 months. And that total number was 22 at the 60-milligram dose, for example. We're only reporting out 14 patients of efficacy because only 14 of the 22 have gotten to the 3 months. So that should give you a little bit of a picture of sort of where the total patient population is within this study.

And then the second question you asked, I'm not sure I captured that.

So I was just thinking like with patients and cystoscopies, like after being on treatment with -- getting on treatment with these patients, once on therapy, if approved, would they continue to require any more manipulation or procedures?

It's a great question. And recall -- yes, recall that we did test whether the value proposition holds if you still need to do 3 months cystoscopies, and patients very much agreed that it did. But you can imagine a future where we're bending the disease-free survival curve meaningfully that the need for 3-month evaluation could be reduced to 6 months, 12 months even. That's already happening in practice today. After a series of 3 months evaluations, if you're not seeing recurrence, you start to look 6 months and then 12 months.

So in a future where patients are well managed with an oral, you can imagine that guidelines might adjust -- physicians might adjust their practice to say, "Hey, you have a really low likelihood of recurrence based off of the data, and therefore, let's look at you every 12 months potentially going forward". So that would be a huge additional advantage of an oral that really can't be achieved with any of the other intravesical approaches.

Our next question comes from Robert Driscoll with Wedbush.

Congrats on all the data here. I wanted to ask about the ablative setting cohort that's going to be evaluated here at 70 mg. I guess, the amount -- the expected number, size of patient lesions and really what you're going to be looking there for read-throughs to the Phase III adjuvant study and maybe even the UTUC study as well.

Yes. Thanks, Robert. As a reminder, we're just looking at the 70 milligrams for the ablative, not adjuvant. 60 milligrams will be our go-forward dose for adjuvant. Within this study, we have the option of opening an additional dose cohort up to 30 patients. So that's exactly what we'll do with the 70 milligrams. We're going to be completing the enrollment in 60 milligrams quite shortly. And so while the study is open, this is an opportunity to then evaluate 70 milligrams potentially for ablative.

Now, we've talked about this before in the UTUC setting, where we said maybe a higher dose is needed to debulk tumors. This has always been a hypothesis. And so when we think about IR NMIBC, if you wanted to use the drug to debulk tumors, getting this data around 70 milligrams could be helpful. Now, we think it's a much smaller part of the market. The broader market is going to be the adjuvant post-TURBT, post evaluation of the lesions that have been removed to confirm that they're low grade and intermediate risk, you would go forward with an adjuvant treatment.

In the ablative setting, there may be some patients that want to forgo surgery and would be willing to take a treatment that does a higher dose could be appropriate to debulk the tumors, and given that they're not having to go under surgery, that there could be a benefit. But we expect this to be a relatively small part of the market and the opportunity.

And just to be clear, we all heard in the UroGen ODAC, FDA had some concerns around the sort of ablative approach and single-arm approach, and most people have moved to adjuvant because that registrational path is more clear. So we would also want to get clarity on the registrational path before moving forward with an expansion in ablation after we get this data with the 70-milligram dose.

We have time for 1 more question, and that question comes from Allison Bratzel with Piper Sandler.

So first, just a follow-up to Dr. Silva's comments about multifocality adding to complexity of disease management. For the company, could you talk to any considerations on whether this data on single versus multiple baseline lesions has any effect on how you define the adjuvant Phase III population, just given the drug's activity was different between those populations?

And then separately, mechanistically, what do we know about why PRs convert to CR at 6 months instead of 3? Is there any relationship or do you think there's any relationship between exposure level, time of conversion? Any color or thoughts there would be helpful.

Yes. Thanks, Allison. On the first question, for your benefit, we actually highlighted in the swimmer's plot baseline marker lesions -- baseline lesions and marker lesions. And when you evaluate that, one of the things you'll see is there are patients with multifocal disease, 8 lesions that are cut out, brought down to 1 that have a CR on our drug. And so it's not so much what you started with. It's how many lesions you left behind that is a key driver of what we're seeing in the signal between single marker lesions and multiple marker lesions.

This would have been the same for THOR-2, a single marker lesion doesn't mean that you only had 1 marker lesion at the start. Many of these patients did have multiple lesions at the start. It's just the debulking, and then, the remaining single marker lesion, which gives you the signal that you've got enough drug on board to be adjuvant. So for an adjuvant setting, the single marker lesion is the closest approximate because in an adjuvant setting, you have 0 marker lesions. You removed all of the tumor. So the single marker lesion we anticipate being very predictive in the adjuvant setting, just like was sort of the hypothesis in THOR-2 and why we make that direct comparison.

Now, why do PRs convert to CRs over time? An oral drug with systemic exposure is fundamentally different. We're getting at the tumor systemically. And the amount of drug on board that's sufficient to keep tumors from growing could take a little bit longer to shrink those tumors, and we saw that in the THOR-2 data. 72% of patients had the CR at 3 months, and it took till month 12 to get to an overall CR rate of 89%. But the beauty of that data shows that a PR, that means lesions shrunk more than 50% with no new lesions arising is clear indication that the drug is working. And even if it takes longer in the ablative setting, in the adjuvant setting, you already have the signal at 3 months with your ORR that you have enough drug on board to be effective.

So if we just look at our ORR across single lesions and multiple marker lesions, 79% ORR is highly predictive of success in the adjuvant setting. If we look at the single marker lesion, we're able to say, of course, we're hitting the benchmark of THOR-2-like efficacy because that's the lens through which THOR-2 is designed. So both of those data points are adding to a very high confidence moving into the adjuvant setting here.

We do have time for another question, and that question comes from Ellie Merle with Barclays.

Just from a safety perspective, can you elaborate on the transaminase elevations and what was seen in the study overall versus what was deemed treatment related? And I guess, your confidence in the safety profile, particularly as it relates to both NMIBC, but also achondroplasia?

Yes. Thanks, Ellie. Let me have Doug answer this question.

Sure. So we're extremely encouraged and -- with the overall safety profile. The toxicities related to transaminase elevation, as you can see by the table, there's a cutoff of 10%. And so we're dealing with low frequencies of transaminase elevations overall. And it was a very good sign at this point that we haven't seen this being a major safety issue so far for patients on treatment.

Yes, Ellie. And ultimately, we think that translates very well. As we talked about, no safety signals through that dose level 5. We are -- we remain very confident on the therapeutic index for the doses we're testing in achon.

This concludes the question-and-answer session. I'd like to turn the call back over to Todd Harris for closing remarks.

Thank you, and thank you, everyone, for participating today. We are absolutely thrilled with what we're seeing. For the first time, we have this really deep data set across multiple efficacy evaluable and safety evaluable patients with dabogratinib in this population, predicting a really high likelihood of success of moving our 60-milligram dose forward in the adjuvant setting. This, we believe, will be a paradigm shift and a game changer for patients, 70% of which are voting with their feet today cannot undergo intravesical urethral violation for effective treatment. Offering an effective treatment that is an oral, we believe, will absolutely change the game.

We're thrilled about our path forward to move this into a Phase III next year and to continue to obviously monitor this data and for our broader dabo 3x3 strategy with the important data points that are going to be coming up in achondroplasia as well as additional patients in UTUC. This is really the first evidence across the dabo 3x3 strategy. We've got a proof of concept. We've got our dose, and we're excited to move forward.

So thanks, everyone, for joining. Look forward to following up with many of you one-on-one after this.

Thank you for your participation. You may now disconnect. Good day.

[Audio Gap] care conference in very toasty Las Vegas. I'm very pleased to be up here this morning with Todd Harris, Chief Executive Officer of Tyra Biosciences. Todd is going to run us through a few slides, and then we'll open up to Q&A. So Todd?

Thanks, Jason. It's great to be here. Thanks for having us. So I will be making some forward-looking statements today. Excited to highlight just upfront here what we talk about -- when we talk about Tyra and our dabo 3x3 strategy. It's a very exciting year for us. It's a very exciting few years coming up for us. We have 3 potential blockbuster indications. Going into late-stage development with our lead drug, dabogratinib, a drug that has been validated in a Phase I study in a late-line metastatic as being a highly selective, very well-tolerated FGFR3 selective inhibitor. It's touched over 100 patients today.

And in the 3 indications that we're talking about, these are validated indications where FGFR3 inhibition has already demonstrated very meaningful outcomes, but where the current drugs by inhibiting other isoforms have run into significant toxicity challenges. It's where dabogratinib can truly stand apart. And to just highlight these indications, and they're quite compelling.

In urothelial carcinoma, there's about 80,000 new patients a year. There's 700,000 patients worldwide with bladder cancer. FGFR3 mutations, and they're very specific ones, drive nearly half of these. But in the intermediate risk setting, low grade and in the low-grade upper tract setting, 75%, 70%, 80%, 85% rates of FGFR3 positivity. So this is where the disease is really driving, or where the gene target is really driving the disease, and it's exactly the gene target that we hit. These are really large opportunities, and we'll talk about it.

In addition, FGFR3 is the driver alteration, the over-expression of FGFR3 that drives achondroplasia and several other skeletal conditions. Combined, these represent really meaningful opportunities to change the game for patients and to change patient care. We are, in many instances, the first-in-class and the potential best-in-class treatment option that could be delivered here.

So let's actually start with what would be the biggest opportunity for us. It's the intermediate risk NMIBC indication. And just to highlight the scale of this, we're talking about 35,000 new patients a year that are FGFR3 positive that could be addressed. This is actually a really comparable size of the market that a very successful drug called osimertinib or Tagrisso targets. There, EGFR-positive lung cancer, there's about 33,000 new patients a year in the U.S. The average treatment duration of that drug is about 23 months. The average treatment duration we anticipate for dabogratinib is also going to be about 2 years.

That drug Tagrisso, osimertinib is about a $7 billion drug. And it's truly changed the game for EGFR-positive lung cancer patients. That's the type of opportunity we're talking about here when we talk about the intermediate risk NMIBC. And let me just highlight a little bit more about why. And to do so, I really want to focus on the patient journey, and I'm going to ask the audience and those listening to go through an exercise with me.

I want you to imagine 30, 40 years from now, you wake up one morning and you see blood in your urine. That's the first diagnosis of a potential bladder cancer. Now you're going to call up your primary care doctor. They're going to tell you to get to your urologist. You're going to look at your urologists and realize, okay, they're probably over 30 minutes away from my house, you're going to schedule an appointment and you're going to show up in the office. And when you show up in the office, the diagnosis will look like this.

You're going to be asked to lay out on a table. You might have a young nurse put the cystoscope up through urethra after a little bit of numbing cream. And then while you're there live, the physician is going to look around and see the bladder cancer lesions and give you that diagnosis. Now you go home at that point, and it's pretty daunting. You look up, you see that survival rates if you're in the metastatic setting can be very poor. You see that if you're muscle invasive or even high risk, you may lose your bladder. And you see that in the intermediate risk setting, you are not necessarily going to lose your bladder, but the recurrence and the frequency of procedures can be quite intense.

Obviously, you're hoping for the best case. The physician is going to go ahead and schedule you for a treatment to remove the tumor via TURBT. You're going to come back 2 weeks later. You're going to lay out on the table, fall asleep. And when you wake up, the physician will have used one of these devices to selectively cut out with a hot wire, each of your tumors collect them. And at that stage, we still don't know necessarily what grade you are. The physician is going to send that out for pathology, tell you to go home, rest, and give you a call maybe a week or 2 later.

So in a great scenario, you're going to get the news from the physician, good news, you're intermediate risk. That means you have a low risk of progression. The challenge with your disease is that you may need frequent repeat procedures if you continue to recur. It's at that setting that we hope to really change the game for the patient. Today, all you're offered is a wait and see and a repeat surgical procedure. Or if you want to tolerate it, you could be invited to come back once a week for 6 weeks, once a month thereafter, to get catheterized by that young nurse and to have chemo pushed into your bladder, and to be asked to sit there for hours on end, potentially trying to hold it in. And then do that week after week after week with potentially even modest results, but a huge burden on the patient for going in. And actually, the scarring and the end result on the bladder itself, this can lead to just fibrosis and a significant deterioration of the bladder.

Now in today's setting, there are new treatments coming. Now all of these treatments involve urethral violation. ZUSDURI just got approved. This would be a once-a-week push chemo gel instead of chemo into the bladder. CG Oncology is looking to advance cretostimogene. This will be a once-a-week pushing of viral vectors through a catheter into the bladder, potentially quarterly thereafter, maybe reinduction with once a week for 6 weeks as well or J&J, which is pursuing the TAR-210 pretzel, which involves inserting and removing every 3 months a pretzel that stays with you every -- really every minute of every day. And it's something you feel it's something that create urgency, UTIs and other challenges.

If we are successful, one day, a physician will be able to say, after your TURBT diagnosis and low-grade diagnosis, I could drop ship you a drug, just take a pill a day, and we'll just monitor you over time, but this has the potential to reduce your recurrence. So hopefully, I've been able to articulate why what we're doing could mean so much for changing standard of care for patients.

Now the reason we believe and we benefit immensely from some of the leading work that J&J did with erdafitinib is that erdafitinib, provided at a lower dose, showed a great CR rate in a study that looked at marked lesions in the intermediate risk setting, 89%. And for any patient that could stay on drug, the durability was 100%, which is remarkable. But mechanistically, actually makes sense. Once the tumor has been reduced, as long as you stay on that drug, you put daily pressure to keep those lesions from growing back.

Now the challenge with this drug was the tolerability, and it was the tolerability due to the FGFR1 and 2 associated tox, things like hyperphosphatemia, eye disorders, nail disorders, mouth stores. That led to dose reduction in 61% of patients. Despite that, even with dose reduction, you saw this good activity. So J&J moved to put this into the pretzel to get local delivery that reduced the systemic tox, which is a great outcome. They got to an 81% 3-month CR, so they were able to get to similar levels of efficacy, and they've advanced this now into their MoonRISe study, their Phase III.

But when we look at what it looks like to have some of these intravesical therapies, or even the pretzel place in the bladder, you can see that these are still associated with significant local AEs, things like 48% frequency, or 44% UTI, or they need to drink 1,500 milliliters of water, or the issues with the urine becoming a biohazard after these events. So these are certainly not a walk in the park.

We are in a current study, and we updated our guidance today to highlight that we're going to read out in August an initial data set here, where we're looking at 2 doses, 50 and 60 milligrams. These are the doses that we believe correspond in their AUC coverage to that efficacious dose that erdafitinib used of 6 milligrams in the THOR-2 study. We'll be reading out at least 10 patients of efficacy at each dose and quite a few more patients that have been on the drug for safety.

We've enrolled well over 20 patients to date. We continue to enroll pretty robustly. So come August, we anticipate that we'll have at least 10 to 15 efficacy readouts. That's 3-month CR as well as a detailed update on safety for likely well over 30 patients in the study. So really important data readout that's coming. This is going to be the determination of a go, potential no-go to Phase III. If we need to test another dose, we can, so we can either move the dose up or down at that stage, if we feel like we're not quite getting there. And the mark we've set for us is really hitting a 70% CR rate or better with the type of tolerability that we saw at these lower doses in our metastatic setting.

Now the unmet need here is truly procedural burden and surgical burden. It's really only an oral option that can address that. The THOR-2 data sets the precedent with exceptional durability of 100% and that daily pressure on the tumor. With our SURF302 study, we want to hit that 70% CR rate or better. We want to repeat the safety signal that we saw in 22 patients treated at either 40 or 60 milligrams in our metastatic setting. To us, that would be a huge success and a go decision for Phase III.

A lot of investors ask us why is 70% enough? One important thing to keep in mind is this is a window of opportunity signal-seeking study. We intend to move into a Phase III in an adjuvant setting where we're not going to be looking at CR rate. We're going to be looking at disease-free survival. The expected disease-free survival at 2 years by doing nothing, which is often standard of care today, is about 60%. You can have about 40% of patients recur. We anticipate with a compelling hazard ratio, getting to a 78% disease-free survival or better would be an exceptional outcome.

And really, the minimum bar here is all we would need to show is that for these patients that have been able to stay on drug for 2 years that we've reduced the risk by 45%. That's a 45% 24-month CR rate. If we hit that 70% 3-month CR rate with excellent durability as we expect and patients can tolerate the drug out to 2 years, we have a high degree of confidence we can have a very successful Phase III outcome in an adjuvant setting.

One final point on the intermediate risk setting is just this. A lot of folks ask us about what about the reimbursement, Buy-and-Bill is a strong incentive to use these procedures in this setting. Well, the reality is in the community urology setting where 70% to 80% of patients with intermediate risk NMIBC are treated. Many of these community urologists now have their own in-office dispensed pharmacies where they've contracted with UOGPOs, so they can have a spread on oral drugs, just like they do for Buy-and-Bill. That's led to a giant increase in their practice revenue coming from oral drugs, especially drugs like Xtandi. And some patients are seeing upwards of 50% or more of their revenue coming from these oral drugs today.

So there's a strong incentive for the physician. It's a strong incentive for the patient. It's really great alignment. And really no one's brought an oral treatment to bladder cancer in this setting before. We've got the oral prostate cancer drugs being used in this setting very successfully. This will be, I think, a game-changing and revolutionary first.

So just a couple of other points before we get to Q&A. We had our first patient dosed in UTUC that we announced today. This is very exciting. This is actually a study that we anticipate moving to our first approval. That's because the registrational path is a bit more straightforward. Jelmyto was able to get to full approval with a 70-patient single-arm study.

A little bit about this disease. It's a rare disease, about 3,000 patients, 85% are FGFR3 positive. What we're talking about is the same lesion in the bladder that drives non-muscle invasive bladder cancer, intermediate risk, but the low-grade lesions showing up in these ureters and the renal pelvis where it's very hard to access with surgical devices. Most tumors are missed, leading to many patients, nearly half getting a nephroureterectomy, or their kidney removed. Where treatments are used, it's in an effort to save the kidney or to spare the kidney, but you still see high rates of recurrence because of how hard it is to actually access and remove these lesions.

One approved therapy is the chemo and the Jelmyto. This had a CR rate of about 58%, a duration of response of 56%. So about 1 in 3 patients are actually benefiting. You can see here, this isn't without a lot of challenges this bag and a hole that's essentially drilled through the back to try and get the chemo into the renal pelvis is not comfortable or easy to deal with. It's only addressing a small number of tumor sizes.

When people ask us, why is this a blockbuster opportunity, a drug like Jelmyto is only doing maybe $100 million, $125 million in sales. There's really a few key drivers. One is Jelmyto priced like chemo and a gel. There's certainly premium pricing here that we're seeing in the high-risk setting that's very acceptable to spare an organ. So I think you can look at a 4 to 5x increase in potential sales with a premium and innovative product. Additionally, only about half of patients can really be addressed with the with Jelmyto because if your tumor is bigger than 15 millimeters or if you're in the ureter, you're not indicated. So now you're talking about an opportunity that's potentially 10x what we would see with Jelmyto.

The last thing is really the ability to change the patient experience, not just in the first year, but for years on end. This could become a prevalent population of patients that have truly spared their kidneys and all the comorbidities associated with that. That would stay on drug, not for just a year, but potentially multiple years as an oral drug stays off recurrence. So we're in this study for 303, we're guiding to initial data next year. We're testing 2 doses, 1 dose overlaps with the IR NMIBC setting, one dose that's a little bit more.

Finally, in achondroplasia, just highlight that we had an exciting announcement today. We are cleared on our fourth dose. That means we have kids, at least 3 or more that have been dosed at each of the doses, the 4 doses we're testing in our safety sentinel cohort. It means that the patients that -- or the kids that have been going into cohorts 1 and 2 are now eligible to be receiving any of these doses when they come up for treatment after their 6-month run-in. And we'll be reading out a 6-month efficacy dose response analysis from the safety sentinel in Q4 of next year.

We shared something really quite interesting and exciting. This is an early scientific experiment, but it showcases what FGFR3 selectivity can do. This was data that one of our scientists shared this past week prenatal dosing in an achondroplasia model. Synchondrosis when -- these are the -- essentially the growth plates of the foramen magnum, are often fused at birth. We see this preclinically in the animal models. What that means is that, that foramen magnum stenosis that can lead to significant surgeries in these kids that contributes to the 50-fold to 100-fold increase in cy and infant death syndrome is really driven by something that happens late in the third trimester.

So we actually treated pups and their moms with dabogratinib in the third trimester and where wild-type expectation for synchondrosis fusion is zero0. When you look at this model of pups with achondroplasia, the synchondrosis fusions are up in the 3s to 4s. With treatment with dabogratinib right after birth, we see a nice reduction. But if you combine that with prenatal testing and after birth treatment, you see that on the far right, you can see we've almost entirely normalized reducing or removing fusion of the synchondrosis in this animal model. So really exciting and compelling result that could be achieved with an FGFR3 selective drug.

So that's that. It's a great setup for data and opportunities. And Jason, happy to answer questions.

And boy, do we have them? Thanks for the great presentation, Todd. Maybe to start, you've outlined what you're looking for in the readout in NMIBC. Can you help us frame what sort of safety profile is ideal, particularly given sort of this is an elderly population. They tend to be a little bit more frail because they've been smokers.

Yes. We like to point to a data set of 22 patients that were treated at either 40 or 60 milligrams. These are metastatic patients from our SURF301 study. That -- there was a rate of low-grade diarrhea, about 18%. We had noted one ALT event was a 5% that was increased. Really nothing else of significant concern there, very low grade 3 events. So that's the type of profile that if we can replicate here now in the intermediate NMIBC setting would be just a huge success.

Now investors ask us, well, that seems like -- what about the diarrhea is not problematic? One thing we point to is you can look at -- there are several studies that Xtandi has done versus placebo. This severe similar elderly patient population. And obviously, it's males, not females. But placebo rates of low-grade diarrhea are upwards of 20% in some studies. So getting to something around 20% is a huge, huge success. And that would be, again, repeating what we've already seen in that UC setting. Low rates of ALT/AST is important. If you look at [indiscernible] Inlexzo, these are local treatments. The AST/ALT increases were 15% to 16%. So obviously, we would want to have very low rates, certainly that look no worse than that. And we anticipate from the data we've already generated, we should be able to do that.

Got it. dabogratinib, again, if you were to, looking at that data, 60%, I believe, dose interruptions, 80% dose reductions. What do you need to come in at compared to those rates?

Yes. We didn't have any dose reductions or discontinuations at our 40, 60-milligram dose. Now that's not to say that in a large study, we wouldn't expect any in the pretzel study, the TAR-210 Phase II update, the discontinuation rate was about 10%. So we would be looking for low rates of discontinuations or dose reductions.

Maybe one more on patient preference. You see a lot of puts and takes. Certainly, I think an oral option for males would be maybe a lot more preferable just given the physiology. But by the same token, some of our docs are talking about, well, if a patient is older, maybe just do the TURBT because their quality of life, or their length of life left just isn't long enough.

What's the sweet spot for you? And realistically, I mean, how much of the market share do you think an option like dabo can capture if it delivers -- it performs as you expect?

Yes. A key point we like to highlight is that we intend to run an adjuvant study. An adjuvant study means, yes, you're going to stage grade the patient with TURBT upfront and make an assessment as to the benefit of then adding on a therapy, right? If you're adding on an intravesical therapy, intravesical chemo, it's not done a lot today because it's so bothersome. That same analysis may occur for a pretzel, or for intravesical viral vectors.

If you're adding on an oral option at that point with the benefit of reducing the likelihood of coming back for a TURBT, you could see how this option would be very favorable, not just for patients, but even for the physicians and their workflow and their practice as well.

Makes sense. Remind us again about how many patients are diagnosed at least in the adjuvant setting? And again, if the option becomes available, you think some physicians might hold a patient if they're kind of on the edge there of the border?

Yes. There's 80,000 new patients diagnosed with bladder cancer. So the majority of those are going to be in the NMIBC setting, low risk, intermediate risk, high risk until you do the TURBT, you're not necessarily going to know precisely what you got. So that's obviously a large amount of new patients every year.

But in addition to that, 750,000 patients living with cancer, and many of those are going to fall in those recurrence groups. So when we look at just the annual addressable population, we think it's conservative to say that 35,000 new patients seeking treatment every year with FGFR3-positive low-grade intermediate risk disease.

Makes sense. Let's pivot to UTUC. Maybe taking a step back, you've outlined, I think, a pretty compelling opportunity, but this was a shift from metastatic UC. Why is this sort of a better sweet spot for dabo relative to maybe the broader population in nmUC?

There's a really interesting phenomenon that occurs when you look at this population, which is a selection bias away from FGFR3 being the driver as you get into more invasive disease. You could almost interpret that. So in the metastatic setting, it's 15% to 20% are FGFR3 positive, but in the low-grade intermediate risk setting, it's 80% plus. So what's going on?

Well, there aren't 30,000 new FGFR3-positive metastatic patients showing up. They're showing up with low-grade lesions. To me, that says FGFR3 is a sufficient alteration to start to drive low-grade lesion outgrowth. And then you typically look in the metastatic setting, there's a lot of co-mutations. So there's other things you're adding on to start to break that low-grade out into maybe something that's high grade or muscle invasive and metastatic. That all points to the best place to start with an FGFR3 selective inhibitor is in the patient populations where FGFR3 is the primary driver in that intermediate risk setting.

But the only way to play there is to have a very selective drug with exceptional tolerability. Because otherwise, these patients want to live their lives. They are burdened by the treatment paradigm of urethral violation, the repeat office visits. You want that oral to be extremely well tolerated so it can just fit into their daily routine, then you really changed the game for that patient.

Jelmyto, 58% CR rate, I mean, ideally, what do you think dabo can deliver here?

So we've tested in market research and what we were really surprised by in the UTUC setting where you're at risk of losing your kidney is that any meaningful CR rate, whether it's 30%, 50%, 70%, physicians will use the oral option first before anything else. The way they look at it is, if I can address this with an oral option, I can avoid all the surgery, remove the kidney, all the other procedures. Why not start there if it's not working for the patient, we've got other options.

So what will drive obviously increased market opportunity would be the more patients getting to CRs and the more that they stay on it for a long period of time, that obviously grows the market. So we'd love to see that be an excellent CR rate, but anything 30% or higher, our market reach for success will get massive uptake because of this being such a preferred option to what they're facing today.

It's fair to say that maybe efficacy should be around what we see from the upcoming NMIBC, sort of?

We're starting to hear this dialogue from investors, and I think it's a wise one that that's a really meaningful derisking event for UTUC because there isn't a reason to suggest it should be too different. There's experience with THOR-2 in the intermediate risk NMIBC setting that was 89% CR rate, that's exceptional. There's experience with erdafitinib in the UTUC space by Surena Matin.

Now it wasn't as clear cut. They weren't all low-grade lesions, but 3 out of 5 patients in that study were spared in nephroureterectomy. They saved their kidneys. And the response rates, even though they weren't all CRs were upwards of 60%, 70%. So yes, I think you can expect this is an equally or similarly responsive lesion. So data in the NMIBC setting can be a really important derisking event for UTUC.

Got it. SURF303, I know a little bit of ways away, but help us frame sort of what benchmarks you're looking for and what kind of output would make you feel comfortable about moving forward in UTUC?

Yes. As I mentioned, the CR rate can be lower here, 30% or better. We are testing a higher dose because efficacy could matter more. And the willingness to tolerate some safety effects is higher given that the alternative maybe you lose your kidney or you end up with a pulling your back in a bag to put the chemo gel or some pretty invasive surgeries.

Got it. Time we have left. Let's go to achondroplasia. If you talk to most prescribers, AHV seems to be much more secondary. I mean, yes, there's quality of life issues. But for them, it's really the medical sequela associated with that sacrococcygeal spine and the bowing and whatnot.

So based on the mirroring data, how much do you think dabo could improve upon those metrics? And what does that look like to the competitive field now, understanding we're still waiting for some data?

Yes. So I think the mirroring data gives us really exceptional hope that if you tune that FGFR3 activity back towards something that's more typical, that you can really very early on, start to normalize many of the growth parameters across craniofacial, foramen magnum stenosis, spinal stenosis and obviously, the long bones, which will drive your AHV surrogate endpoint.

BioMarin just shared some really exciting data, and it looks like they're going to go to the FDA to get full approval, which is great. And that data shows that over time, that AHV benefit that seems to be maintained for multiple years starts to lead to meaningful changes in proportionality, tibial bowing. So what's exciting for us is if we can start to hit an AHV difference from placebo, that's more typical of actually changing this to someone without achon.

And that -- for us, the target is you want to hit about a 2.7 centimeter per year, not the 1.5 to 1.7. So it's almost a doubling of the AHV. That should directly lead to faster time to hitting these endpoints, could even give us an opportunity to see in a 12-month randomized period, actually hitting endpoints that others haven't. So we're really encouraged by that data. We're obviously looking at what are those endpoints that we might now look at in that 12-month randomized setting if we're really hitting the AHV mark that we want, which is to nearly double it.

Got it. Maybe a little bit premature, but let's throw this out there. Do you think that level of growth could drive maybe premium pricing?

Yes. I think a little premature. Obviously, we've seen what TransCon has done with their pricing. We'll see what BridgeBio does. I mean, look, this is -- we're looking to really provide the best-in-class solution. And there's already, I think, a great market here. Our market research, yes, suggests you could offer a slight premium by obviously beating these benchmarks. That's something that could go into consideration. But really, the focus is on -- for us, it is important with this program that we demonstrate best-in-class activity. We'll be the fourth to market. So that that's necessary to be successful here.

Well, with that in mind, last question, help us frame the output end of the year. What are we looking for to make you confident you're best-in-class?

It really comes down to at the highest dose or the highest 2 doses, beating the benchmark set by others at 6 months. Those AHVs were in the low 6s for BioMarin, for Ascendis in the high 6s for BridgeBio. So we're looking for a dose response curve that clearly points us into the 7s, potentially 8s at that 6-month period.

Perfect. Todd, thanks so much for joining us.

Thanks, Jason.

Appreciate it.