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

Good day, ladies and gentlemen, and thank you for standing by. Welcome to the Tyra Biosciences' conference call to discuss the first patient dosed with TYRA-300 and the SURF301 study. As a reminder, this conference is being recorded. Now I'd like to turn the conference call over to Amy Conrad from Investor Relations. Please proceed.

Thank you, Jamie. Good morning, everyone, and thank you for joining us. With me today from Tyra are Todd Harris, Chief Executive Officer; and Hiroomi Tada, our Chief Medical Officer. Also on today's call is Dr. Jonathan Rosenberg, Chief of the Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology and the Enno W. Ercklentz Chair of Memorial Sloan Kettering Cancer Center. For those of you participating via conference call, the slides are made available via webcast and can also be accessed by going to the Investor Relations page of our website following conclusion of today's call. Todd will provide introductory remarks and will review the outsized market opportunity for TYRA-300 and bladder cancer. Hiroomi will discuss our clinical plans for TYRA-300 with SURF301, and Dr. Rosenberg will provide context on the patient journey in unmet needs in bladder cancer. Then we will open up the call for your questions. Before we begin, I would like to remind you that this call will contain forward-looking statements concerning Tyra's future expectations, plans, prospects, for strategy and performance, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. In addition, any forward-looking statements represent our views only as of the date of this webcast and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements. Now I'll turn the call over to Todd. Todd?

Thank you, Amy. Welcome, everyone, and thank you for joining us. Right now is a really exciting time at Tyra. We initiated our first clinical study, SURF301 and have dosed our first patient with TYRA-300, our FGFR3 selective inhibitor designed to be agnostic to the gatekeeper mutation. This is a significant milestone for Tyra, which marks our official transition to a clinical stage company. As you can imagine that the achievement of this milestone, our conviction in TYRA-300 continues to grow. It's the first program stemming from our in-house SNAP chemistry platform, which is purpose-built and designed to overcome tumor resistance in oncology. Our platform is rich in opportunity, and each one of our assets was designed to be best-in-class within their respective indications. TYRA-300 represents our largest opportunity with blockbuster potential in bladder cancer. To help frame out this opportunity, we're excited to have Dr. Jonathan Rosenberg joining us on the call today, Jonathan is a world-renowned GU medical oncologist and key opinion leader, who has run some of the most important clinical trials in bladder cancer, including for emerging targeted therapies. He will touch on the broad opportunity of FGFR3 agents in bladder cancer, the overall patient journey, and the current approach is to address the unmet medical needs. With that, I'll turn the call over to Jonathan. Jonathan?

Thank you so much for the introduction, and it's a pleasure to be here to talk about FGFR3 in bladder cancer. The FGFR3 protein is mutated across the spectrum of disease states in urothelial cancer, both in upper tract and in bladder tumors. This is quite common in up to 70% of non-muscle invasive bladder cancers, particularly noninvasive tumors. And these tumors frequently recur but rarely progress and actually represent the most common form of the disease, for which there is no targeted therapy that is approved and in part because the toxicities of existing treatments prevent them to be used regularly in patients with non-muscle invasive disease. For muscle invasive and metastatic bladder cancer, mutations and fusions of FGFR3 occur anywhere from 12% to 20% of patients, depending on the trial that depending on the data set you look at. And this has been validated as a clinical target in urothelial cancer based on data from erdafitinib, which I'll talk about in a few minutes. Also, a significant unmet need is upper tract urothelial cancer, which have very high rates of FGFR3 mutations. About 92% of low-grade tumors and 60% of high-grade tumors in the standard of care for many of these patients is nephroureterectomy. And while people can live with 1 kidney, it's better to have 2, and an agent that would be able to target this alteration might lead to clinical benefit and reduction in need for invasive surgeries in patients with advanced -- with locally-advanced upper tract disease. Next slide. FGFR inhibition has been shown in several trials to be active. We see here data from infigratinib, formerly known BGJ398. This is a study in advanced urothelial cancer status post patient -- patient status post platinum chemotherapy. Then we see that with this agent, the response rate was 25%. Many of these responses were durable up to a year and that there was activity regardless of the type of mutation or alteration that was observed. And this drug has not been approved in urothelial cancer but is now approved in other indications, but represented the first completed trial that showed data that -- the target was relevant. Next slide shows the erdafitinib data from the pivotal trial that led to the accelerated approval. This is from BLC2001, showing that 40% of patients responded to erdafitinib with confirmed response with progression-free survival and overall survival of 5.5 and 13.8 months, and that many patients were on treatment well past 1 year. We have not seen the data updated again in manuscript form, and we await the randomized Phase III trial data from this agent to see whether or not this will receive full approval. But these data supported the first FDA approval of a targeted therapy in advanced urothelial cancer. Next slide. Unfortunately, pan FGFR inhibition, which is whether erdafitinib is and what infigratinib is, lead to many more side effects than one might expect with a selective FGFR3 inhibitor. In particular, these are toxicities associated with erdafitinib, central serous retinopathy and retinal pigment epithelial detachments, which are generally reversible, do occur in about 1/4 of patients. Diarrhea is common. Fingernail changes, while not serious or life-threatening, certainly are uncomfortable and having patients lose their fingernails as a quality of life impediment. Stomatitis with FGFR3 inhibitors has been very difficult to manage and while, again, not necessarily life-threatening, remains a substantial decrement in quality of life. In addition, the electrolyte abnormalities that result from pan-FGFR inhibition, including hyperphosphatemia and hyponatremia, can limit treatment for patients who receive these agents. And while these may be manageable, certainly require more attention from the physician and the patient and significant dietary changes to be able to stay on medication. Next slide. There was a pilot study that we conducted with Sloan Kettering with infigratinib, sorry, as a treatment for non-muscle invasive bladder cancer. It was a marker lesion pilot study that ultimately only was able to accrue for patients. I think the study was before it's time. But interestingly enough, we saw ablation of tumors in 3 out of 4 patients who received FGFR3 inhibitor for a period of about 9 weeks prior to their first assessment, and so I think this establishes at least proof of concept that in a non-muscle invasive bladder cancer setting that an oral agent that's an FGFR inhibitor would have activity in non-muscle invasive bladder cancer, and I think leads us to potential future opportunities. What we also saw in those patients was that toxicity was difficult and that all the patients essentially came off for toxicity rather than treatment failure. And the longest treatment was about 4 months or so. And so I think with that, that sets the stage for where we are with FGFR3 inhibition in urothelial cancer, and I'll turn it back over to Todd and Hiroomi.

All right. Thank you, Jonathan. We founded Tyra with the simple mission to discover and develop next-generation drugs in target oncology to deliver benefit of patients and to patients. On Slide 12, we're showing an example of one of these patients that developed resistance to currently available therapies. This patient had an FGFR2 positive intrahepatic cholangiocarcinoma, they were given infigratinib. They saw a nice initial response and ultimately, that patient recurred occurred and with the recurrence coincided a single amino acid shift. And as you can see on Slide 13, the single amino acid shift occurred in the active side of the FGFR2 protein, which you see here is where infigratinib advised in the back pocket. The gray space model represents the large steric side chain of the phenylalanine coming through the [ dimethoxypyrimidine, ] infigratinib, and this is the gatekeeper mutation, and it significantly reduces infigratinib potency. This issue is not isolated to infigratinib. All of the approved Pan FGFR inhibitors have used the same dimethoxypyrimidine, to access the back pocket. And as a result, all of these agents have a liability for gatekeeper mutations, which has now been seen clinically in many patients. As we move to Slide 14, we'd like to highlight -- this isn't a new story. We saw the resistant story emerge with EGFR therapies, where the first-generation drugs achieved progression-free survival of about 10 months, but then patients recurred with the T790, gatekeeper mutation in the back pocket. Osimertinib is designed to overcome this and was able to rescue patients who recurred after treatment with first-generation inhibitors and in the head-to-head study that nearly doubled progression-free survival in 19 months, which was encouraging to see. On Slide 15, we really highlighted in the last 5 years, we've seen that extended progression-free survival repeats across multiple targets, most recently with repotrectinib, ROS1 is a target by addressing the resistance of the first-generation drugs by improving tolerability. The FGFR agents in development are showing limited durability improvements over the prior generation. We know there is a huge opportunity to do so by addressing acquired resistance. TYRA-300 was designed to overcome both the major limitations of first-generation inhibitors with selectivity for the gatekeeper mutation and with selectivity for FGFR3 over other isoforms. As we move to Slide 16, we want to highlight that we believe an FGFR3 collective inhibitor like TYRA-300 has the potential to address an outsized market opportunity with accounting for key factors that drive precision oncology revenues. Returning to the osimertinib examples, in non-small cell lung cancer, as you can see in the top row here, there are nearly 200,000 incident patients in the United States. Around 15% of those patients have the EGFR mutation, most of whom are eligible for treatment with osimertinib now that it is an approved agent in the adjuvant setting. With this efficacious and well-tolerated profile, adjuvant patients stay on therapy for close to 2 years on average, and these factors are combined with leading market share resulting in $5 billion in 2021 sales for osimertinib. Alectinib is approved for frontline metastatic non-small cell lung cancer. And with only around 2% of patients driven by all alterations, this therapy still generated around $1.5 billion in 2021 sales. As we go to FGFR3 and urothelial cancer, there are approximately 80,000 incident patients in the United States with urothelial carcinoma. And it's estimated about 50, 5-0, percent of these patients have an FGFR3 activated mutation. Based on annual incidence and percent alteration alone, it is clear that the opportunity for an FGFR3 selective agent like TYRA-300 is outsized relative to other oncology targets. As we move to Slide 17, though we are initiating TYRA-300 clinical developments in late-stage patients, we believe there is significant opportunity to serve unmet needs in earlier stages of the disease using an FGFR3 selective agent. In the intermediate and high-risk non-muscle invasive bladder cancer setting, 25% to 30% of patients treated with adequate intravesical chemotherapy and BCG have been shown to relapse within a year from treatment, and outcomes for many patients treated with less than adequate therapy are worse. BCG-resistant patients can be treated with the immunotherapy that many are ultimately referred to an oncologist for cystectomy or bladder removal. Patients with muscle invasive bladder cancer can be treated with neoadjuvant or adjuvant chemotherapy, but ultimately 30% to 50% of radical cystectomy patients will relapsed with metastatic disease. Toxicities remain a challenge across the metastatic setting, including chemotherapy, ADCs, erdafitinib and emerging PD1 ADC combination. The patients who relapsed from erdafitinib have no targeted option to address the commonly arising gatekeeper mutation. We believe an efficacious, well-tolerated small molecule FGFR3 inhibitor has the potential to meaningfully address unmet needs across the stages of the disease treated by both urologists and oncologists, either as monotherapy or as part of a combination regimen, and we have alignment with the FDA that after establishing initial proof of concept of safety and efficacy in late-stage patients, we can open up earlier stage NMIBC cohorts. With that, I'll turn the call over to Hiroomi to discuss TYRA-300 and SURF301 in more detail. Hiroomi?

Great. Thanks, Todd, and good morning, everyone. I'm really excited to discuss our lead candidate TYRA-300, which is the first oral FGFR3 selective inhibitor in development today for urothelial cancer. So as Todd mentioned, TYRA-300 was designed using our SNAP chemistry platform to be selected for FGFR3. This is actually a challenging engineering problem that we have to solve because amino acid sequences from [indiscernible] the actions are actually nearly identical. We started by overlaying the molecular models for FGFR1 and FGFR3 and identified subtle areas within the active site where we felt that we can drive higher FGFR3 selectivity over FGFR1. This was followed by dozens of candidates that were co-crystallized in high-resolution structures of the various FGFR family members. And what you can see on the right is a cross section of one such area where we were able to push deeper into the pocket of FGFR3, where FGFR1 was more constrained. We did this in multiple areas of the [ active side ], and that led to greater selectivity for FGFR3 over FGFR1. Then on the next slide, what you can see is the results of all of this work in the profile for TYRA-300. We do a lot of competitive profiling, and it's critical to our next-generation candidate design process. This slide shows that using a collection of Ba/F3 cell lines that are driven by either FGFR1, 2, 3 or 4. And the top table shows the IC50, the different inhibitors against each of the different FGFR family members as well as TYRA-300 high potency for FGFR3, which had an IC50 of around 1.8 nanometers. The bottom table shows the full selectivity for the other FGFRs over FGFR3. You can see that all of the approved agents have similar or identical FGFR1, 2 and 3 activity, even though FGFR3 is the target in urothelial cancer. In some instances, you can see that there's some separation for FGFR4 like with pemigatinib and infigratinib. But importantly, TYRA-300, we see double-digit fold separation across all of the family members relative to FGFR3. And I'll emphasize again that FGFR1 is associated with hypophosphatemia. FGFR2 has been shown to cause dry mouth and stomatitis, keratitis, skin and nail toxicity, and FGFR4 has been associated with those with GI toxicity that includes diarrhea and liver toxicity. So any efforts to create a more FGFR3 selected drug has the potential to hit the target harder and reduce toxicities that have been a challenge in this class of drugs. On the next slide, you can see that we have in vivo data that confirms TYRA-300 selectivity over FGFR1. In a preclinical rat experiment, we measured serum phosphate levels 24 hours after a single dose of either erdafitinib or TYRA-300. And as you can see, there is a dose-dependent increase in serum phosphate after a single dose of erdafitinib, whereas we don't see an increase in serum phosphate with similar doses of TYRA-300. And here on the next slide, what we show is an vivo model using the human UM-UC-14 bladder cancer model, which is driven by an S249C mutation, which is the most common mutation in bladder cancer. TYRA-300 has good antitumor activity with both a 9-milligram DID and 18-milligram QD dose. It's important to note that we are treating at a lower dose than with erdafitinib at 12.5 milligrams BID. So we believe we're starting to expand the window of efficacy and safety against the approved agent in this preclinical model. Now on the next slide, as Todd mentioned, TYRA-300 was designed to be active against the gatekeeper mutation that arises in patients that are treated with an FGFR -- there, we're showing on the left-hand side an FGFR3 TACC3 fusion in a human bladder cancer cell line RT112. All of the approved agents in TYRA-300 have low in nM IC50s against the wild-type FGFR3 that you can see in the gray box. But importantly, when we crisper in a gatekeeper mutation, you can see that all of the other agents, except for TYRA-300 fall off several hundred even thousand fold in activity. And lastly, on the next slide, we show that the potency of TYRA-300 against the gatekeeper mutation is reproduced in vivo. On this slide, you can see that both TYRA-300 and erdafitinib have good antitumor activity against the TACC3 fusion cell line on the left, which is the parental cell line. But on the right-hand side, in the presence of the gatekeeper mutation. TYRA-300 maintains antitumor activity, whereas erdafitinib is now ineffective. So all of this preclinical work has led us to the point now of bringing TYRA-300 into the clinic in our Phase I/II study, SURF301. We've chosen, and given that power is a San Diego-based company that's near a lot of great surfing spots. But the study also stands for study in untreated and resistant FGFR3-positive advanced solid tumors. And on the next slide, you can see SURF301, which is an international multicenter open-label Phase I/II study. The Phase I portion consists of 2 parts with the goal of determining the maximum tolerated dose and achieving the optimal Phase II dose for later development of TYRA-300. Part A above will enroll patients with any solid tumor regardless of FGFR3 mutation status so that we can determine the MTD as quickly as possible. Part B below will enroll FGFR3-positive patients in multiple dose expansion cohorts to explore the inhibition of FGFR3 relative to the other family numbers. So the design of the study is once we clear those where we believe we're starting to inhibit FGFR3 in Part A will begin to enroll additional FGFR3 positive patients in backfill cohorts in Part B. At the same time, while we're dose escalating in Part A. This will give us multiple doses to evaluate the biomarker and efficacy endpoints to fulfill some of the guidance that FDA has outlined for project [ Optimis. ] We believe that FGFR3 inhibition may not be dose-limited and a maximum tolerated doses may actually be due to inhibition of other FGFRs such as FGFR1 or FGFR2. So the design of the Phase I is to help ensure that we're not necessarily choosing the maximum tolerated dose, but one that we believe most optimally balances efficacy against FGFR3, and tolerability by sparing FGFR1 and FGFR2. So SURF301 is currently open and enrolling adult patients with advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations. We're really pleased to report that the first doses in SURF301 were administered at Macquarie University in New South Wales, Australia. And as this is an international study. It's a real privilege to have many sites such as Peter MacCallum Cancer Centre, Memorial Sloan Kettering, the University of Washington, Cleveland Clinic, Institut, Gustave Roussy, [indiscernible] and Dana-Farber working with us to advance the study. So in summary, we're really excited to evaluate TYRA-300 in the clinic, and we're working hard with our sites to identify and have more patients so that we can deliver an important therapeutic option for patients with urothelial cancer. So with that, I'll turn it back over to Todd for closing remarks.

Thanks, Hiroomi. Before we open the call for questions, I want to communicate the enthusiasm we have for our robust pipeline. We feel we have tremendous momentum leading or heading into the end of this year and into 2023. We are now a clinical-stage company with the first oral FGFR3 selective agents to be evaluated in the clinic, uniquely positioned to capture an outsized opportunity in bladder cancer. We plan to be thoughtful about the way we read our data, read out data from our SURF301 study, and we'll keep you updated on our plans as our data mature. Each of our other programs has the potential to address meaningful opportunities and design the best-in-class therapies within their respective indications, including our FGFR1/2/3, inhibitor TYRA-300 and programs for 800 plays at FGFR4 and RET. We remain well capitalized with $263 million in cash at the end of Q3 2022. Tyra is in our strongest position yet as a company, and we look forward to continue to innovate and target oncology with our purpose-built therapy. Operator, we're now ready for questions.

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

So clinicaltrials.gov states that you're starting at a 10 mg once daily dose, I believe. So can you remind us how that compares to the 12.5 mg per kg dose used preclinically in xenograft models? And perhaps most importantly, to what extent will you be able to dose escalate in humans and what dose level in humans do you think will be therapeutically active?

Thanks, Tyler, for the question, and a great question. I think it's important to highlight because we did compare directly with erdafitinib. The approved dose for erdafitinib is actually less than 10 mgs. And so for comparing directly here, this is a reasonable starting dose. But certainly, we expect to learn different information about exposure as we move through different animal models and the human being a unique one. So I think we're going to wait for the data, understand exposure. And as Hiroomi indicated, we'll continue to dose up. And as we see exposures that we think are relevant in terms of having FGFR3 activity is when we'll start to expand. So this point, we're going to wait and see the data, I think, before we make any strong assumptions about which dose will ultimately be the optimum or recommended Phase II dose.

Okay. That's helpful. And I wanted to ask on just a second topic. I guess, so efficacy in Part B is fairly straightforward, I suppose. But what biomarkers will you be looking at specifically? And how should we interpret them as we think about the selection of the recommended Phase II dose?

Hiroomi, do you want to take this question?

Yes, absolutely. So as you may know, FGFR3 is actually quite challenging from a biomarker standpoint. We know what the biomarkers are for FGFR1 inhibition. For FGFR3, there is literature to indicate with the FGFR3 monoclonal antibody, that urinary MMP1 might actually be a good marker for FGFR3 activity. So we're going to look at both serum and urine biomarkers across a spectrum of platforms to see if not only MMP1 but other potential markers may be regulated in response to TYRA-300. In addition to that, we'll also be collecting serial ctDNA samples from both plasma and urine to look at changes in circulating tumor DNA to really help us understand in a much earlier time point whether or not we're having an antitumor effect. And then we're also looking at skin biopsies where you may know that in skin, FGFR 1, 2 and 3 are being expressed in different parts of the skin. And so the skin biopsies by doing digital spatial profiling, we'll be able to actually determine when we're starting to inhibit FGFR3 relative to the other FGFRs in a dose-dependent fashion. So we think that we have a robust biomarker strategy to really understand the biology here as well as to optimize the dose relative to the toxicities.

Our next question comes from Geoff Meacham from Bank of America.

This is Hao calling in for Geoff Meacham, and thanks for the question. So I want to say congratulations on this important milestone. So my first question is given the commercial erdafitinib, which is more FGFR2, 3 inhibitor, do you see there's a need to block both FGFR2 and 3 to achieve antitumor activity in urothelial cancer? And if you have any preclinical data to support that blocking FGFR3 only is sufficient? Hello? Can you hear me?

Sorry, this is Todd. I can take this call, but I just want to start off by thanking Jonathan Rosenberg, and I know he's going to need to run to the clinic. So I want to go ahead and release him and I thank him for his contributions. As we -- yes, thank you, Jonathan. So for the specific question about whether or not it's valuable to also block the other FGFR isoforms, I think the best data we can share there is what Hiroomi walks through today, and that is 2 well-validated bladder cancer cell lines, one the UM-UC-14 and the other the RT112, both of which have been validated as FGFR3-driven cancer cell lives via CRISPR. And as we look in our own preclinical models, it's clear that with an FGFR3 selective agents like TYRA-300, we get really good antitumor activity. And that's compared, of course, to erdafitinib, which is a pan-FGFR. That's, I think, the strongest data we have that suggests that these really are driven by FGFR3, and it's the molecular alterations that are either fusions or the dimerizing mutations that's our driving these cancers.

Great. That's helpful. Just another quick question. So it looks like the FGFR3 mutation in noninvasive blood cancer was much higher like 70%, while in metastatic urothelial cancer was 20%. So any reason why the difference of percentage-wise and also if you wanted to move into earlier stage blood cancer, what would be the safety bar required to enable moving into the early line of the bladder cancers?

Yes, 2 great questions. I think with the first question, the best answer is it's not clearly known. I don't think there has been conclusive data to explain why that frequency potentially goes down. Of course, you can imagine that as tumors get more invasive, they may be acquiring additional mutations that help them advance. But ultimately, we know that the incidence with FGFR3-positive mutations in earlier stages of disease are quite high. And as you talked about the bar here, standard of care in NMIBC in the earlier stage of diseases is BCG installation, which does come with side effects and a pretty high burden in terms of patients' visits to urologists and really treatment costs in managing these patients over a very long time as they continue to recur. And so an agent that is potentially well tolerated that can be taken daily as an oral medication, that could essentially spare that cost and burden of frequent appointments to urologists, but also and most importantly, the cost ultimately of recurrence, cystectomies and metastatic disease, we think is really exciting and really important for patients. And with a safe and tolerable treatment, I think that's really the bar. And improving the convenience for these patients, I think, could make an agent -- an FGFR3 selective agent like TYRA-300 potentially an excellent treatment option for these patients.

Great, and congratulations again.

And our next question comes from Maury Raycroft from Jefferies.

This is Kevin on for Maury. Congrats on the update. Just the first question, I guess, for Todd. You mentioned that you spoke with the FDA on opening up earlier cohorts. Could you just clarify whether that would be for non-muscle invasive or also for muscle invasive? And then you talked about adequately establishing the safety and efficacy. Do you have any specifics on when that could be? Could that be after the recommended Phase II dose? And did you discuss a specific efficacy bar as well as safety?

Yes. Great questions, Maury. I'll hand it over to Hiroomi to answer this question and specifically related to correspondence with the FDA about NMIBC.

Thanks, Todd. So I think what's important is that the risk benefit for metastatic disease is very different than it is for the earlier settings. And so FDA was clear with us that they wanted to see some initial efficacy data in metastatic patients before we moved into recurrent non-muscle invasive bladder cancer. So really, it's around establishing that we have a drug that has anti-tumor activity that's well tolerated before going into earlier lines. And in terms of your second question, remind me what that was?

Just if you're -- if it was muscle invasive as well as non-muscle invasive, and then -- yes, sorry, go ahead.

We do have some thoughts around muscle invasive bladder cancer, whether or not it's a potential window of opportunity study. We haven't -- those plans haven't fully matured, but we think that there are opportunities for a well-tolerated drug to be used in settings where we can really do some important biologic work as well as dose ranging in these earlier lines of bladder cancer.

Okay. Great. And then just a follow-up on enrolling the study with sort of the current landscape around genetic testing capabilities. Do you have any line of sight in terms of what you expect the pace of enrollment to be at [ MSK ] and then at other sites as well?

So we've specifically gone to institutions that do a lot of NGS testing, and that was very purposeful to be sure that these sites were able to identify potential candidates for the study. In addition to that, we are using liquid biopsy to help screen patients, and so we believe that, particularly in the metastatic resistant population that rather than putting patients through tumor biopsies that a liquid biopsy will really help in terms of identifying these patients much more quickly. So that's -- part of our strategy is, again, to go to sites that do this routinely, but also to provide an additional testing mechanism that broadens the patient pool.

And our next question comes from Mitchell Kapoor from H.C. Wainwright.

Just wanted to ask how could you potentially pursue a tumor-agnostic strategy versus tumor indications? And how could those strategies look different if you see activity in one or more...

All right. Thanks, Mitchell. I think one thing to highlight that in our Phase I/II design, we do have a cohort for tumor-agnostic patients. We do rely on next-generation sequencing that is now increasingly occurring across multiple sites and hopefully ultimately multiple indications to help recruit into that study. And we have seen some initial data from erdafitinib, for example, that was published earlier this year in a tumor-agnostic setting. And so we would follow a similar path within that cohort to evaluate patients not based off of their tumor type but based off of FGFR3-positive disease using some of the standard activating mutations and fusions that are seen in bladder cancer and have been validated there.

Okay. Great. And what kind of learnings can you take from the development of other therapies that address gatekeeper mutations such as osimertinib. Is there anything that helps guide your thinking of clinical development?

Yes. It's really a great question, and we shared some information on other targets and agents in the material today. We do that because we think that data are becoming increasingly clear that agents that address acquired resistance have the potential to improve or extend progression-free survival. And I think one way to help validate this is it's important to show upfront that when you have a gatekeeper mutation, for example, in a patient that is starting to recur, the ability to bring some of those patients back into a response or at least stabilize their disease provides strong evidence that moving earlier online has some potential in a naive patient population to move the progression-free survival even further out by essentially preventing that acquired resistance when we think it would occur. And so we take that approach across our indications and thinking about addressing acquired resistance and the benefit that next-generation inhibitors might have progress for extended progression-free survival.

And our next question comes from Jennifer Kim from Cantor Fitzgerald.

Hey, team, congrats on entering the clinic and for the helpful presentation. I just have a few questions here. The first is more of a competitive question. You're a bit ahead in development of another FGFR3 selective inhibitor from [ Lilly, ] and I think they're entering the clinic maybe before the end of this year. But are there any key differences you'd highlight for your selective asset or differences in the way you're approaching your clinical or development strategy? So for example, I know they're including a PD-1 combo arm already. And I'm wondering, does that change the timing of when you could start exploring a combination?

Jennifer, thanks for the very thoughtful question, and I think it's important to start off by saying that we encourage drug developers next-generation therapies for patients. I think this is more options for patients, better agents that can improve outcomes. It's really what our collective goal is here. So it is good, we think, to obviously see other activity in this space for the benefit of patients. It's hard today is where we stand to compare our agents relative to theirs is there's pretty limited data out there on Lilly's agents. Whereas obviously, with some of the approved or later stage development assets, we can do some of the more direct comparisons. So I won't comment too much there. And then on clinical study design, I think as Hiroomi indicated, we really highlighted the Phase I portion here, which is to move as quickly as possible to an optimum recommended Phase II dose, understand the MTD. But we will and intend to move pretty quickly as well in exploring potential combinations and other ways that we can really progress TYRA-300 in the treatment paradigm here coming out of that initial Phase I readout. Hiroomi, anything you want to add? Sorry. Hiroomi, did you want to add anything there?

Yes, sure. I think that we wanted to provide ourselves with some optionality as well. We have the potential to -- as soon as we have an optimal Phase I business, we can very easily amend the protocol to add a PD-1 cohort. But at the same time, we may want to go through a broader strategy of combining with different PD-1s and really help us understand sort of the landscape and help us with potential business development. So I think that there are a lot of things that we want to be able to do. We haven't made them explicit yet as we're still relatively early, but I think that PD-1 combinations as well as combinations with other novel agencies is really part of our development plan.

Okay. And then one quick question. Have you said that the total number of clinical sites you anticipate for the trial?

So for Phase II, I believe that will have a total of about 18 sites across the U.S., Australia, France and Spain. And then for Phase II, we're in the process of doing the feasibility.

Ladies and gentlemen, with that, we'll be concluding today's question-and-answer session. I'd like to turn the floor back over to Todd Harris for any closing remarks.

All right. Thank you, again, for joining us on the call today. We're extremely excited about our recent progress. We look forward to see our momentum in advancing our entire pipeline in the New Year. Operator, ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect. Goodbye.

And ladies and gentlemen, with that, we'll conclude today's conference call and presentation. We do thank you for joining. You may now disconnect your lines.