Tyra Biosciences, Inc. (TYRA) Earnings Call Transcript & Summary

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 Phase II 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. [indiscernible] 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 uterus 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 [indiscernible] Phase II 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 installations, 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 in 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 [indiscernible] 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 installations. 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 neurology 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 [indiscernible] 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 set. 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 [indiscernible] 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. [indiscernible] 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 [indiscernible] 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 [indiscernible] 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 installation to work for 12 months could be very quickly in the pursuing 12 months. And [indiscernible] 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, [indiscernible] you have a very safe dose that covers IC50. What do you think that means for development of achondroplasia? That's it for me.