Tyra Bioscience Aktie

[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.

Hi, good morning, everyone. I'm Ellie Merle. I'm one of the biotech analysts here at UBS. Very excited to have Tyra here with us today as part of our fireside chat series of achondroplasia. Joining us from Tyra is Todd Harris, CEO; Alan Fuhrman, the CFO; and Doug Warner, CMO. Guys, thank you so much for making the time.

Just a brief disclaimer before we begin. As research analysts, we are required to provide certain disclosures relating to the nature of our own relationships at UBS with any company on which we express a view on this call today. You can find these disclosures at ubs.com/disclosures or reach out to us, and we can provide them to you. If anyone has any questions, they'd like us to ask, feel free to shoot me an e-mail, and I will do my best to get to it.

With that being said, guys, thank you so much for making the time today. Maybe just to kick it off, can you give us sort of an overview of Tyra and your pipeline?

Sure. Ellie, thanks for having us, and hello, everyone.

So Tyra is a company with a focus on structure-based drug design and the FGFR family, our SNÅP chemistry platform, we've made all of our molecules from scratch, including TYRA-300. TYRA-300 is unique as really the first selective FGFR3 inhibitor to make it well into the clinic now. We've shared Phase I data in a late-line cancer population that highlights really the potential of this approach which is reducing some of the toxicity associated with FGFR1, 2 and 4, which can be quite troublesome, and hitting that target, which is quite meaningful actually. If we look at -- on the oncology side of the house, there's nearly for...

We're loosing you a little bit, Todd.

Wait you're back, you're back. It was the speed of the internet. I think we can hear you now.

Yes. Largely in the intermediate risk setting for NMIBC. And on the skeletal conditions, the skeletal display side of the house, we have achondroplasia, where we're now in our BEACH301 Phase II study as well as other skeletal dysplasias, where we estimate there's nearly 40,000-plus kids in the U.S. alone with open growth plates that have an FGFR3-related conditions. So some very large opportunities with a highly selective molecule, TYRA-300 plus other programs in oncology, including TYRA-200 and 430.

Great. Well, a lot to discuss. So maybe starting with TYRA-300, maybe how does sort of our FGFR3 inhibitor mechanism compared to CNP in addressing the disease biology in achondroplasia?

Well, achondroplasia is a condition that's driven by a mutation in FGFR3 and it's known that, that mutation directly causes over-expression or over activation of that gene.

So hitting that target directly, of course, makes a ton of sense. The primary role of FGFR3 is to act as a negative regulator of chondrogenesis or a break on chondrogenesis. So when it's over-expressed, it essentially stunts the normal process of physiologic growth.

And by modulating or inhibiting it, you can essentially restore what would be a typical phenotype, both in the growth plate and at least in our preclinical models, you see a more typical phenotype across all of the clinical sequela and growth parameters. There's really strong genetic preclinical and our clinical data that highlights FGFR3's role.

On the genetic side, we know kids with achondroplasia, they're on average going to grow about 4-foot-3 if you're male versus 5-foot-9. But there's also conditions of FGFR3 mutations that are essentially a knockout phenotype, a syndrome called CATSHL, for example. And in that situation, males are going to grow 6-foot 5 or about 10% taller.

That's -- because it establishes the genetic role of FGFR3 from an overactivation or under activation perspective as being a key regulator of growth across the spectrum. We now have preclinical data with TYRA-300 showing its ability in achondroplasia, hypochondroplasia, and even in wild-type animals that with suppression we can generate further long bone growth.

And then we actually have really good clinical data as well that highlights the effect of FGFR3 inhibition at very strong doses and that would be in kids that have pediatric cancers. Going on full FGFR inhibitors or full oncology doses of FGFR inhibitors, where they see really remarkable growth as much as 19 centimeters per year on average versus the 7.6 centimeters on average you'd see in a typical phenotype. But that's driven or inclusive of complications of over growth. So full suppression of FGFR3 can drive really rapid growth, but it can actually drive growth too far.

So when we look across all of this evidence in all of these parameters, really clear FGFR3 is a master switch. It's a really meaningful target. And so of course, the TYRA-300, that's exactly what we're looking to do initially in achondroplasia, but in other growth conditions as well. is directly and selectively hit the FGFR3 target.

Yes, that makes sense.

And I think that oncology data on the over growth, I think it's like an interesting data point that people don't talk about enough because I think it's like -- and we should talk about what the ideal amount of growth, and at what point you're achieving normal? And are we there yet of some of the compounds or not? And how much further there is to go. But still, I think is important proof of concept for the fact that a lot more growth is possible through this mechanism, And we've seen that in the clinic in oncology.

But let's talk about FGFR3 selectivity. And I guess, why this is important? And I guess, how you use this to inform the therapeutic window?

Yes. So FGFR3 selectivity is important because FGFR is a family of 4, FGFR1, 2, 3 and 4, and all of the FGFR's have a really important physiologic function.

So with FGFR1, it's a regulator of phosphate, among other things, in the kidneys. And with FGFR2 plays a pretty important role in growth of nails and some of the salivary glands, lacrimal glands. And so as a result, what we saw initially with the pan-FGFR inhibitors that hit both FGFR1, 2 and 3 is that when you get the doses up to full engagement, simultaneous engagement of 1, 2 and 3 you see phosphate levels rise in 80% plus of patients. You see 60%-plus patients getting really problematic nail issues when their nails are falling off, mouth sores, eye tox and PPE.

So making an FGFR3 selective inhibitors, it's actually -- it's a pretty obvious idea because you obviously would want to avoid those toxicities. The challenge is it's a very hard engineering problem. People have tried it with large molecule formats, antibodies, but especially in the indications we're going after a small molecule clearly is needed to directly inhibit that activation and get into the growth plate and a small molecule selective FGFR3 inhibitor is really something that no one had done before. And so TYRA-300 was really the first to make it in the clinic. It was the first to be designed that way. And how does I think, a really important place as a result?

So when we hosted BridgeBio last week, they pointed to the fact that like the trade-off might be, okay, maybe you have less selectivity for FGFR1, 2 and 4, but maybe you hit other components such as FLT4. Can you talk about the profile here?

Yes. I think that comment is driven by a lack of understanding of the structure of the FGFR family. So the homology is really close between 1, 2, 3. And so making a selective molecule that separates from 2 and 1 is a very, very challenging problem. But 4 is a kinase that you often see with a lot of -- it's inhibited by a lot of kinase inhibitors with drugs like selpercatinib, which is a selective RET inhibitor, among many others. Usually seen enzymatically and upon follow-up you really just don't see any activity cellularly and then clinically, which has certainly been the case for us.

So we think this on a kinome scan, much like many molecules that you see, it's important to follow up and demonstrate that you don't really have any anticipated effect or side effects, which is certainly what we've seen as we followed up both in cells and clinically.

So this TYRA-300 retains an exceptional selectivity profile. And I think the most important focus clinically has been that the side effects are driven by FGFR1 when you're treating with pan-FGFR inhibitors, and that's something where we now have a very strong body of clinical data with 100-plus patients now treated with TYRA-300 where we've been able to show strong FGFR3 activity, while sparing FGFR1 and 2 and not seeing nearly the level of AEs that you would see with a pan-FGFR inhibitor. As it relates to phosphate increases, as it relates to stomatitis, the mouth sores, nail toxicity, eye toxicity or PPE.

So really, I'd say this is a very validated approach now with TYRA-300 that we've proven with our initial Phase I data.

Yes. Can you compare TYRA-300 selectivity and the potency for FGFR3 like relative to other FGFR inhibitors such as BridgeBios, but also maybe some of like the other attempts in the past to target FGFR3?

Yes. And we ran an experiment that we published in our corporate deck, it's very clear one where we -- and this is actually run by an external vendor. We leverage Ba/F3 cells. So this is a cellular experiment, that are driven either by FGFR1, 2, 3 or 4. We actually did it head-to-head against infigratinib and the 3 approved pan-FGFR inhibitors at the time futibatinib, pemigatinib erdafitinib.

What we show there is nearly identical activity between FGFR1, 2 and 3 for the pan-FGFR inhibitors, but with TYRA-300, we have high potency for FGFR3 and more than an order of magnitude separation and that cellular activity for FGFR3 versus 2, FGFR3 versus 1 and FGFR3 versus 4.

So that really is the key preclinical evidence for us that we leverage, then followed up, of course, by preclinical in vivo models and now clinical data.

Yes. Interesting. Okay. Yes, I saw in your deck, but it's compelling in terms of the selectivity. So in terms of the disease, can we talk about sort of like what this means from a therapeutic window perspective? Like, what is the ultimate goal for what in achondroplasia, like the amount of growth we should be looking for?

Yes. So what I already talked about or articulated is that full suppression of FGR3 can drive a level of growth in kids that is quite simply too much. You see fractures and other challenges by pushing the limits way beyond what's seen physiologically.

What we have now seen though is multiple data sets evidence that if you can, through a growth stimulating therapy, whether that's growth hormone, whether that's CNP plus growth hormone or vosoritide in kids that don't have an FGFR3 alteration, you can see kids growing at 8, 8.5 centimeters per year very safely.

And that's a great target that we just haven't seen yet in achondroplasia, all of the agents, whether it's TransCon CNP, vosoritide or BridgeBio have been able to get kids to about 6 centimeters per year in terms of annual high velocity from a baseline of about 4.

And so moving that really doubling that efficacy is what we're looking to do here by engaging FGFR3 in a way that no one has yet.

Okay. So like we don't want to get to 6 centimeters here. We want to get to like 8 to 9?

Yes. There's ample evidence that's a safe amount and there's ample evidence that with that FGFR inhibition, you can push it, quite frankly, if you go too high of a dose, you would likely push it well beyond that. And so we want to obviously -- our Phase II dial, the right dose that optimizes a target that's in the line with about 8, 8.5 centimeters per year.

Right. So we know the mechanism can get you to that growth, if anything, much higher, but it's about if you have the therapeutic index to do so.

Maybe let's talk about the preclinical data that you've shown then in achon sort of, can you give an overview of what you've seen so far, including some of the recent preclinical data you had at ENDO?

Yes. So I think what excites -- and when we talk to the community, when we talk to parents of kids with achondroplasia, physicians that treat them, what -- when they see the profile of TYRA-300, and then they see the result in some of the achondroplasia, hypochondraplatia and other models that we've shared.

What they get most excited about is the direct data we're able to see in those models are changing, for example, the area of the foramen magnum or changing the bone volume and bone density or changing the histopathological structure of the growth plate. In addition to, of course, just elongating the bones, which is a metric that comes along with all of this as well.

So all of that's seen in these very breast preclinical models, which is, I think, the most exciting part for the community of what an FGFR3 inhibitor should be able to do.

And can you maybe talk about sort of like how you're -- I mean, I know it's hard to compare preclinical data but just like how your preclinical data on growth and maybe any other like comorbidities like the foramen magnum might compare, say, to infigratinib or even VOXZOGO, and TransCon CNP?

Yes. The data on TransCon CNP and VOXZOGO was pretty limited in these models, not nearly as effective as FGFR3 inhibition. With TYRA-300 versus infigratinib, we've never ran it head-to-head, but we've given the molecule of the same lab [indiscernible] in the studies with the 2.

And what we consistently see is that at doses that we anticipate getting to in the clinic in BEACH301, levels of exposures we anticipate getting to with BEACH301 and target engagement that we anticipate we have a therapeutic index to get really superiority across all of the metrics.

Now you can -- infigratinib did a high dose and a low dose. I think just to highlight that there was a difference -- there was some activity at a low dose. So you can see that model consistently, we see at the dose that we've tested. This is a dose that we can achieve in the clinic, and we anticipate being able to demonstrate superior outcomes.

But again, the cross-trial comparisons are challenging. You need to understand, can you hit that dose. And so one of the things we tried to articulate is at the dose, where we've shown our data in achondroplasia models. This is a level of exposure that we saw with our 40-milligram adult dose, at that 40-milligram adult dose, we saw no hypochondroplasia -- or sorry, no hyperphosphatemia, no AST/ALT increases and, quite frankly, a pretty pristine safety profile.

So that's what gives us the most encouragement here is an exposure with superior outcomes in a preclinical model that we've now given multiple individuals that same level of dose -- adults and seen really an exceptional AE profile. That's the therapeutic index that you would hope for with an FGFR inhibitor.

And what would be your expect for the doses that kind of the expected therapeutic dose range? What would you expect in terms of like the phosphorus elevation and like the potential for like hyperphosphatemia?

Yes. So we are really anticipating the dose we want to get up to and probably not exceed as an average inhibition of FGFR3 at around an IC50, and that was something that we achieved with our 40-milligram adult dose.

Moving beyond that, when we look at preclinical models, when you look at genetic models like the CATSHL syndrome, you're probably moving into a range of growth or FGFR3 inhibition that is likely exceeding what you want to be or where you want to be.

So when we look at that 40 mg adult equivalent dose. As I mentioned, we have a really pristine safety profile, no hyperphosphatemia, no changes in liver enzymes, really no evidence that FGFR1, 2 or 4 associated talks that you would likely see with the pan-FGFR inhibitor.

Our phosphate elevation is an issue. I mean like we've heard different things right because apparently like they're elevated from the growth hormones like BridgeBio's mentioned like there's physician feedback, that this is very manageable. What's your perspective on that?

Yes. Look, I think what I see in the data that BridgeBio shared to date, I think they have a really nice safety profile. And if 1 child sees elevated phosphate levels, that's something you may just see in a child, 1 in 20 children anyways. They already have an elevated phosphate. So I think the commentary that you're getting is appropriate. The profile they're putting up looks really safe.

Now to do that, of course, they're treating at a dose that's 1/6 of their oncology dose. So they've moved down to a level of FGFR3 inhibition that's a very modest and as you move up beyond the dose that they've seen, they highlight in there, in their protocol that they published in the New England Journal of Medicine that as soon as they get to 0.3 to 0.4 milligrams, they see evidence of elevated phosphate. So they're going to be tipping up phosphate levels quite a bit further if they go above their current dose.

So the level that they're seeing, I think, is very acceptable. I think they've minimized it and done so intentionally. And similarly, we anticipate we will very meaningfully minimize it by going to about half the oncology dose just simply because we don't -- we didn't see it. And we have that therapeutic index by designing the FGFR selectivity that I highlighted from the preclinical data.

Okay. So at the current level is probably manageable, but you're just able to dose higher and hit FGFR3 more. Understood. Maybe can you give us an overview of your clinical trial plans in achondroplasia and the trial design?

Yes. Let me hand it over to Doug Warner, our CMO. Doug do you want to take that question?

Yes, absolutely. So our BEACH301 study consists of 2 components. So the first component is the sentinel safety cohort that's enrolling patients aged 5 to 10. And it's involved 4 ascending dose levels from 0.125 up to 0.5, and 3 children are dosed at each level. And once it clears the safety, the dose has increased. And the primary objective of that, of course, is to look at safety.

And our second component of the trial is enrolling patients aged 3 to 10. That first are enrolled in the natural history lead-in for 6 months, and then are either rolled in 1 of 2 cohorts. One cohort is naive patients, and the other cohort is patients who've received prior growth accelerating treatment. And that as well is dosing at 4 dose levels 0.125, 2.5. And once the dose level clears in the sentinel, that dose level can be enrolled in that second cohort 1 or 2.

Where are you in enrollment?

So right now, we have trial sites to open. We haven't enrolled a patient yet. But we did see some challenges with the protocol of structure.

Todd, I don't know if you want me to elaborate on that or...

Yes, I'm happy to go a little bit further yet. Ellie, we are now in, I think, a really good spot open for enrollment, 3 sites with several others. We anticipate coming online very soon here.

Over the last few months, I think one of the key things as we engage the community, we realized it's a pretty big burden to get on the study, and we had -- we did want to make some protocol modifications so that we could allow families that we're going to be traveling to the sites, which is the majority of families that had sort of opted in and reached out to talk about the study, we're in that position. So made some meaningful adjustments earlier this year to make this really a much less burdensome protocol and family.

So now we're starting to see really significant engagement. I think that the efforts have paid off in terms of a lot of families sort of showing that engagement. With 3 sites open we can direct families to those sites, but with multiple additional sites open, including some of the places where families are currently being treated, we anticipate getting into the second half of the year being kicking this off, I think, quite similar.

Okay. Sorry. Just to clarify, when do you expect to dose the first patient?

We've guided second half of the year. So we are actively, I think, in this -- in a stage where we anticipate we can be in both dosing and enrolling into cohort 1 and 2 in the second half of the year, which we're in.

And I recognize it's a lot easier to judge from my seat behind the computer and not actually run a company or trials.

But like maybe can you just elaborate on some of the hurdles that you face sort of in kind of the site setup or initial patient enrollment?

Yes. I think the first -- as I mentioned, what we learned pretty early on is that nearly all the families are going to be traveling. What we wanted to try and avoid is the need to travel out for months on that, especially with kids in school or going to summer school or summer camp.

To do that, we needed to just decrease some of the visit required. And we heard this from regulators as well as ethics bodies as we kind of went out the gate at the beginning of the year with the protocol we had. So we trimmed down the number of visits nearly in half to make it much more amenable for patients to travel out and get on the protocol. That's probably the one of the most meaningful changes.

The other thing we heard a lot of engagement from families who had prior treatment. Maybe they were on VOXZOGO or had try VOXZOGO, going been on other therapies, wanting to get on the study. So we also -- we had our Cohort 1 and 2 that Doug mentioned. We also made modifications that have now allowed for potential families to even enroll the sentinel safety cohort if they had a prior treatment.

So those I think changes are now starting to really pay significant dividends in terms of just the feasibility for allowing families to get onto the study and TYRA-300.

Yes, I'm a little surprised because I mean I don't know if I had open growth late, I would want the opportunity to be taller, but that might just see me personally. But okay. All right.

The enthusiasm is really strong, Ellie. We're seeing, I think, obviously, the other challenge is just getting some of these academic medical centers open that can take 9 to 12 months after an IND.

So and that's where a lot of these families are really used to going so those are some of the next ones to come online that we think were really making a lot more convenient for some of these families to be on the study.

Okay. I want to ask more questions on the study. But I did also want to ask though when we had a BioMarin on this, they mentioned like an interest in potential combinations, particularly with an eye on selective FGFR3 inhibitors.

I'm curious just from a strategic perspective, how you think about the potential to bring this forward completely on your own, whether you would explore nonexclusive collaborations, partnerships just like big picture what your strategy is?

Yes. Look, we've maintained an active dialogue with all companies and time and respect for BioMarin and what they've done here and really carving the path for treatment in achondroplasia. And I think they've done an amazing job so far.

Commercializing that, and we see the enthusiasm on the parents of having finally an option. So I think it's absolutely great what they're building, what they've done and what others, I think, will do as well with TransCon, Ascendis and ultimately rooting fo BridgeBio success as well in this space. I think having options for these kids is great, and we see that when we interact with community.

Certainly open to partnerships with TYRA-300, and we keep an active dialogue. Could we commercialize this ourselves? We absolutely think so. When we test the product profile we're looking to achieve here, the uptake -- families are incredibly enthusiastic, physicians are incredibly enthusiastic about the idea of doubling the efficacy, right, I mean not just from 4 to 6, but the 6 to 8 and what that means for the other clinical [ sequela ].

So I think with the successful demonstration of that here in BEACH301, there'll be many opportunities for us to consider how we want to commercialize this, whether that's ourselves or ultimately with a partner.

Mechanistically, like what do you think of the combo between CNP and FGFR3. Like do you get enough growth from FGFR3? Like what would that be additive in terms of like a mechanism perspective?

Yes. I mean I think our view here, and this is an informed preclinically. If we just look, for example, at our wild-type models, just with FGFR3 alone, if you give full -- a full oncology dose and you get an IC90 inhibition of FGFR3, you're going to push over growth. And so I'm not sure the combination really makes sense in very many indications.

There could be some, and I'd love to see the scientific rationale, but for FGFR3 driven conditions and then just for an idiopathic growth, I think FGFR3, there's ample evidence genetically, preclinically and clinically that it can do more than enough and that you're actually going to be bringing the dose down to tailor that to a safe amount of growth.

Perhaps there's another condition where CNP genetically and FGFR3 are both altered in a way that the combo makes sense. But I think for the vast majority of the indications, you're going to be able to use an FGFR3 inhibitor. Now if you have a CNP apathy like a CMP receptor issue, then CNP is your right choice. Just like for achondroplasia, hypochondroplasia, I think an FGFR3 inhibitor is ultimately going to be the right choice to optimize the outcome.

For idiopathic, it's probably -- possible you could use either, I think, from the preclinical data that I've seen, CNP seems to work in a wild-type model just like FGFR3, assuming you have the therapeutic index with an FGFR inhibitor.

So from that perspective, it might be the choice between oral and injectable but I anticipate it likely is going to work in both in the idiopathic space. SHOX, I'm not sure. The preclinical data isn't there. So we know that it's FGFR3-driven, so it should respond very well to an FGFR3 inhibitor. How CNPs perform there. I think we're going to have to see the clinical data first.

Okay. No, I think that, that makes sense. So maybe like the combo, and this is my interpretation, but like maybe the combo isn't more as much as achon, hypochon, but maybe as we think about like these much broader indications like ISS like I mean I know right now, most people are focused on achon, but my view is 3 years from now, all these other indications are going to be the much, much larger opportunity set. Maybe that's where combos, where we don't as much understand the biology, it could perhaps play a role. But, yes, I think that's interesting.

Sorry, I got us a little sidetracked. I did want to ask more about BEACH301. Okay, so like what are we going to learn -- so okay, in second half, you're going to dose the first patient. Hopefully, like a good cadence of enrollment and that picks up. What are we going to learn as the trial goes on about the safety? And what kind of updates can we expect?

Yes. I think based off of where we're at today, our confidence is growing around some of the -- at least the initial time lines where we anticipate the sentinel safety, I think first half of next year, we'll have a pretty solid handle on safety. Second half of next year, be able to start to talk about efficacy, which would be kind of initially that 6-month AHV.

And this is 12 kids. Now there's 3 children at each dose level, but we anticipate that the majority of these kids are going to get a level of FGFR3 engagement, it's not achieved with the dose that certainly are currently being used with BridgeBio infigratinib.

So that should mean that a relatively large number of kids would have AHVs that we anticipate to be superior or outperform the initial data sets put up by others at 6 months. So we think that could be a really meaningful data set. And then, of course, we've got our Cohorts 1 and 2 that we'll fill that out. And as we see the enrollment play out, I think we can guide a little bit more to when the time lines for 6 and then 12-month data would be there.

Cohort 2 is going to be really interesting because you're getting patients that presumably were on VOXZOGO now?

That's right. Yes. And we run -- we have an opt-in form where patients are learning about our studies coming on to a BEACH301 trial website and reaching out. And what's been surprising is we've sort of tracked on the background, nearly half kids interested in the study -- the families have tried a prior treatment before. So there's a strong interest. And so we're sort of leaning into that now that the development is like we're going to be in this prior treatment landscape. And I think with the penetration of VOXZOGOs already seen, that makes sense. So being able to demonstrate high-quality data in kids that have been on VOXZOGO before, we think, is going to be super important.

So the safety update in the first half next year, will we get AGV data or too early?

No. I think AGV, that initial data would more likely be in the second half of the year.

Okay. But we'll presumably get kind of some safety updates throughout commentary. Okay.

In terms of the read-through from the BridgeBio study, which like I think at least for your stock, I think, a massive catalyst coming up early next year. What would be like almost a best-case scenario in terms of what you think it means for your clinical program in what we would see in that Phase III data set?

Yes. Look, as I mentioned, rooting for BridgeBio success on behalf of the community that I think is excited about it, kids and giving the benefit. I mean, we've all seen the Phase II data, my sort of interpretation and view is that they have a great shot at getting an annualized like velocity of about 6 centimeters per year based off of that data. I think that's going to be a really solid outcome because it's competitive with the injectables, but it's in an oral format.

So that type of result, even if it's on par, with the CNPs, but well-tolerated oral would be an exceptional outcome highlighting the benefit of direct inhibition of FGFR3, albeit at a very low level of target engagement. And I think that will [indiscernible] for a lot of enthusiasm around further target engagement with an FGFR3 selective compound.

So you expect to see around like 6 centimeters or so of growth, but do you think that we should be really looking for like 8 to 9 ultimately long term?

Yes. I think with BridgeBio expecting 6 centimeters would be the expectation from the data we've seen. And then, yes, getting to 8, 8.5 really provides a great opportunity, I think, to make more meaningful changes on the other clinical [ sequela ] are open for these kids.

What do you think is the biggest risk from a safety perspective from infigratinib at the doses that they're looking at in achondroplasia?

From what we've shared publicly, this looks like a well-tolerated drug at that 0.25 mg/kg dose, 1/6 of the oncology dose, their level of target engagement is relatively modest for all of the FGFR1, 2 and 3. So lack of clear safety signals, not too surprising. Obviously, you see a more modest growth as a result of being at that low dose.

Makes sense. And so just in terms of kind of like the time lines from TYRA-300 and like the cadence of what we can expect to learn. I feel like can you be a little bit more specific on like what we'll be able to learn around the safety from the sentinel cohort at this update in the first half of next year. Like what influence safety you'll get basically?

Yes. I mean, again, I think I intentionally pointed to the other agents here, whether it's CNP or infigratinib, I think those are safety profiles that are really compelling and good.

Of course, kids may have a sickness here or there, and it may be hard in an open-label study sometimes to determine what drug related or not. I think in BridgeBio data that had some diarrhea, but it wasn't like a dose response across their low to high dose. Had one elevated phosphate I think, in their safety data set, but it wasn't at the highest dose, which makes me think that it's probably not a concern. It's probably something you just are going to see in 1 in 20 kids given the way that lab values are determined with 95% confidence intervals.

So yes, a similar profile for us as others have seen, I think would be a huge success. And then, of course, differentiated on efficacy is the goal.

And then I guess, what are your expectations from a growth perspective when we ultimately get that, I guess, from both Cohort 1, the naive patients and Cohort 2, the ones that, I guess, have been on VOXZOGO in terms of growth. And like what are your expectations there? I mean, honestly, it's just based on the biology and what we've seen in the oncology setting, like it would surprise me if you don't see a much more meaningful uptick in growth. But like, yes, I mean, can you give us specific numbers? Like what do you expect to see at those dose ranges?

Yes. I mean, I agree. It would be surprising based off of the science -- scientific rationale here to not see something. And it's really this is all about this optimization. So what we're looking for is getting to again, that 8 to 8.5 centimeters per year during the window that we're treating new kids would be a really exceptional outcome. That's what we're looking to get with a safe profile.

Moving beyond achondroplasia, which I think is like a really, really interesting topic that more people should be talking about. But like can you talk about kind of the much larger opportunity set where you think that like FGFR3 could play a role. And let's talk about sort of some of like the sizing of these population from a prevalence perspective.

Yes. And look, I cite your work a lot Ellie here because I think you captured the TAM at somewhere around $10 billion, and I think you're not too far off in terms of what that sales are.

That's really just a function -- that idea gives a function of just how many children with open growth plates have a condition where -- whether it's achondroplasia, hypochondroplasia, that includes Leri-Weill dyschondrosteosis as well as Turners. Well that's 20,000 to 30,000 kids in the U.S. at the open growth plates and then idiopathic short stature, which depending on how you define it could be 100,000 kids or it could be even more again into the U.S. alone.

So you're talking about really significant amount of -- a significant population looking at potentially a growth accelerating therapy or a condition modifying therapy in the case of achondroplasia and hypoachondroplasia. There's an expansive growth opportunity. And BioMarin, I think has done a good job highlighting where they're going and why and what this looks like.

I think one of the -- one of the really interesting things, there's been a whole market that's evolved with growth hormone. And the early promise there was giving children to additional benefit in final adult type. The reality is that in nearly every condition except for growth hormone deficiency, growth hormone pushes growth in the first year to 8.5, 9 centimeters per year but attenuates in such a way that it really doesn't have a meaningful impact on final adult height for any of these kids.

So you've got this whole market. I think that's been primed, but without an agent that actually delivers improvement in final adult height. And if you just what we've now shown, for example, in our wild-type animals, where if you give an oral dose of TYRA-300, at the right amount, these animals may grow 8% taller. The long bones are going to grow that level of additional growth.

So this is kind of a master switch to push growth when you need it. And that evidence gives us a really strong encouragement that the market that really growth hormone was never able to actually address could ultimately be addressed, whether that's, again, idiopathic short stature, SHOX mutations, achondroplasia, hypochondroplasia or other.

How do we think about which indications make the most sense for CNP versus which make the most sense for an FGFR inhibitor. And also, like do you need to have FGFR3 selectivity if you go beyond achondroplasia and hypochon? So those are 2 questions, maybe we'll start with the first like how you split it.

Yes, I'll start with the first. So just focusing on our own preclinical data, we have very strong evidence that FGFR3 is the right target. That TYRA-300 is the right drug for achondroplasia, hypochondroplasia, and I would include all of SHOX mutations because that also is a transcription factor that directly upregulates FGFR3. And now with our wild-type data that we published at ENDO and JCI, idiopathic short stature as well.

Now idiopathic by definition means you don't know what's driving the lack of growth. So there certainly could be some kids that might respond better to an FGFR3 inhibitor? And it's possible others might respond a little bit better to CNP if it ends up being a mechanistic -- mechanism that's downstream of CNP versus FGFR3. But across the board, we have a high degree of confidence. FGFR3 will be an oral agent that will be the right target to have a pretty meaningful impact across all of those.

How would you explore like or like think about like what the dosing would be? Like with the CNP is actually have seen that the dosing might even be lower in some of these other indications. But like how would you approach that? And like how does -- what's the therapeutic window in these other occasions relative to achon?

Yes. I mean this is a -- until you do the studies, you have to do the work, you have to do a Phase II. But we try to use a real strong genetic rationale to the dose we want to go up to. And that I highlighted that syndrome called CATSHL, which is -- it occurs in families where one of the FGFR3 alleles is mutated so it's on functional. And I think that's a good recapitulation of what it looks like to have a IC50 inhibition in FGFR3.

And the -- there are some that syndrome. There can be some hearing losses thought to be related to prenatal FGFR3 suppression. The families are relatively healthy, but they're growing 6-foot-5. So it's 10% taller than the average population. You can see some overgrowth in the ribcage with something called pectus excavatum.

That's good representation of, I think, what we would call the limit, and it's why we've designed up to our 40 mg adult equivalent or the 0.5 mg/kg dose in our initial study because pushing it to IC50 should get a great result and probably not tip you into full suppression, which could give you potentially a result that stimulates too much growth that you want to see.

So that's our best guess today based off of the genetic. And again, we published doses down to half the ecology dose where we see wild-type animals, we get statistically significant improvements in growth that, I think, reinforces that idea.

And then now looking clinically, we know kids that have gone on the pan-FGFR inhibitors that for oncology doses are getting to that 19 centimeters per year. That's too much but we also know from our data that half of our full oncology dose at around 40 mg. We have an exceptionally well-tolerated drug while the growth rates are closed. So moving that type of dose, of course, into children with open growth plates, it gives us the best chance at pushing -- exploring the limits of growth acceleration with the selective inhibitor we have.

Great. Yes, really, really interesting opportunities set. In terms of maybe pivoting to oncology, but first, just oncology in the context of what we've learned about the safety profile. Can you kind of walk us through the data that you've had so far in oncology and in particular, the safety profile that's been reported? This is something we get a lot of investor questions on.

Yes. So we started in our SURF301 study. This is a patient population that exhausted all prior therapies, obviously, a relatively elderly population and largely metastatic urothelial.

What we saw is once we got to our 90-milligram dose of exceptional efficacy in this population for the FGFR3-positive metastatic urothelial we're seeing a 50%-plus ORR. But what was most remarkable and the key thing we really want to demonstrate here was the improvement on safety.

And so we looked across metrics like hyperphosphatemia, which would you would expect on a drug like infragrotinib to be about 80% when you hit the oncology dose. That was all the way down into the teens and low grade. Nail toxicity, which would be 1 in 4 patients with dose reduce as a result of nail tox with erdafitinib and it's going to occur in a 60% plus patients.

I think we had 1 out of 15 patients with low-grade nail-disorder, same with stomatitis, 1 out of 15, and PPE, I think it was 2 out of 15. So the ultimate data set here showed across the board, meaningful reduction in the FGFR2 and the FGFR1 associated toxicities, which is really the thesis that we built this drug in the beginning.

So with that evidence -- and then we had also done something in this study where we tested 22 patients at the lower doses with 20 of them receiving 40 milligrams or 60 milligrams at the outset. And in those patients, we had pretty much the -- a 1 out of the 20 that had a grade 1 ALT increase. It's actually a patient whose highest ALT measurement was on baseline before they went on drug, no hyperphosphatemia, no dose reductions and a reductional safety profile across the board.

That's important because that gets us into the window of the max dose. We're going to be using achondroplasia, which would be the 40 mg adult dose but also the dose we're testing in earlier-stage bladder cancer, the 60-milligram dose, where, again, tolerability would be really important. And we have clear evidence that that's a tolerability profile that could be very acceptable for an oral targeted treatment in intermediate risk, NMIBC setting.

Yes. I mean I think you recently announced you dosed the first patient in the SURF302 study in intermediate risk NMIBC.

Can you give us kind of an overview on sort of the competitive landscape there where you think you fit and sort of the value proposition?

Yes. So we are the only company pursuing an oral to targeted therapy here. J&J had tried this with erdafitinib a few years back. Doesn't get the tolerability profile they wanted with the high rates of hypophosphatemia and the FGFR2 toxicities that I just highlighted. So with that in mind, they also saw exceptional efficacy. So they saw an 83% CR rate with that oral drug when they tested this population. So it's clearly that patient population is highly responsive, and so again, with the selective drug, it makes a ton of sense to seek a high degree of efficacy that could be well tolerated and been for multiple years.

Now what you're trying to avoid in this setting are repeat surgeries, and they come with a really high patient burden. This is an elderly population, going -- you're going to need to go in general anesthesia for the standard of care, TURBT surgery. So avoiding that to be a huge benefit. The other competition today are all looking to go after this with a procedural solution.

Now most of these agents were tried systemically and weren't tolerated. So they move these into something that you can insert through the urethra, catheter, whether that's erdafitinib eluting in a pretzel, stent or some of the oncolytic virus approach with CG Oncology or the recently approved UroGen, which is chemo and a gel.

So these are all great options for patients. It's an alternative procedure to the surgery. But if you look at the way that the prostate cancer landscape has evolved in the urologist setting, moving towards oral has really changed the game first for patients but it's also reoriented the practices around a better business model, if you will, for them, where they're able to manage a patient with far fewer -- far less time in the office.

In the surgery room, they're able to avoid the buy-and-bill can be favorable in the sense that they get some spread on the drug, but it can also be challenging because you have to buy all the startup front. Sometimes with full your partners' checks to do so.

On oral, there's a model now where they do in-office dispensing and they get a spread on the prescription and they are able to manage patients with what ultimately is the best therapy for the patient and do so successfully whilst to continue to support the practice economics.

We think that's exactly where bladder cancer is going to go in the urologist office with a targeted oral agent. We're the only ones in development here. And I think it's -- this will be one of our first data sets come out. We're anticipating next year, and I think it's going to be a pretty exciting game-changing therapy for the space.

Yes, it's really -- yes, really exciting. Maybe just can you go into a little bit more detail on the design and specifically the time lines and what we should expect to see from the initial data?

Yes. Let me have Doug handle this one too.

Sure. So we have a Phase II study that's enrolling patients with low-grade intermediate risk bladder NMIBC and also having activating alterations in FGFR3. And so patients are randomized into 1 of 2 arms, 1 arm testing 50 milligrams QD, the other 60 milligrams QD.

And this is a marker lesion study, meaning some of the tumors left in, in order to evaluate response. So the primary endpoint of the study is 3-month complete response. We have secondary endpoints, such as duration of response, recurrent-free survival as well as safety.

And as Todd mentioned, so we'll have some initial 3-month CR data in the first half of next year from both of those cohorts.

Great. And what should we be looking for in terms of like the bar of what would be good data?

Great question. As Todd mentioned, with [indiscernible], they saw an 83% response rate and associated with severe toxicity, given the convenience and preference of an oral therapy, when we talk to KOLs and investigators think 70% CR would be an effective level of activity in the oral setting.

And what's good on safety? I mean it's oncology setting, but I guess, what would be like good safety in that context?

Yes. It is oncology, but if you talk to urologists, they're not exactly like your medical oncologists. So they really want quite a safe, well-tolerated therapy. So as Todd mentioned, at the 60-milligram and below dose, we're not really seeing any significant toxicity in terms of hyperphosphatemia, AST/ALT elevation, dose reductions, that sort of thing. So we anticipate a pretty clean safety profile, the doses we're evaluating.

Okay. Well, we look forward to that update.

Just going back to the safety profile in like achondroplasia and growth disorders because like at least in my view, it's like pretty obvious, the efficacy would work as we've seen from the oncology setting and the pediatrics growing there and what we know about the biology. But just going back to kind of like potential for hitting, say, like FLT4, have you published sort of the kinome scan and like what we -- at least what's out there that can give us confidence, we wouldn't see any other toxicities?

Yes, we did -- we have published the kinome scan. We've published TYRA-300 in both in peer-reviewed paper as well as we've had on our corporate deck, I think for some time in the early days, the kinome scan.

The most important thing to understand, you do a kinome scan, obviously to follow up on any targets that you want to dive into deeper. The only thing that showed up as similar potency to FGFR3 was the FLT4. Next to that, we started to separate very meaningful from FGFR2, FGFR1 and any other targets where orders magnitude separated.

Follow-up on FLT4 really bore for no fruit. You typically see an enzymatic activity for FLT4 like if you look at selpercatinib, for example, which is more potent for FLT4 than RET, when you follow up a molecule like that in cells, you essentially see the FLT4 activity drop significantly off. And that's not surprising because you have a very artificial assay to test all these kinases in a high throughput format. So when you get a hit, you follow up through it.

We followed up on FLT4 and see no activity. We see no evidence of activity preclinically and clinically that this would generate any adverse effects as a result. And so this is a hit in an artificial assay that on follow-up really, there's no concern for us.

There's really no other hit beyond the other isoforms that we've had a meaningful concern around and we've now demonstrated that separation all the way into SURF301, clinically demonstrating a significant reduction on what those might cost. So from our perspective, from our kinome scan to our follow-up in vitro assays and cells are now to preclinical safety models and now to clinically. This appears to be an exceptionally well-tolerated and selective FGFR3 inhibitor, and it's proved that thesis out as we've seen that data.

And it's not always the case that you're going to see that not perfect translation. So even as others look at highly selective FGFR3 inhibitors that are look good in a kinome scan or look good enzymatically that translation also requires all of the other qualities of the drug to allow it to go the distance. It can't be genotoxic, for example, it can't be phototoxic for example. It needs to have really good bioavailability and really good PK characteristics.

And those are the kinds of things that starts to create challenges for Loxo, for example 435, needing 400 mgs twice a day and not being able to get a consistent level of exposure is just one example of the drug properties that can trip up an otherwise good selective inhibitor.

So this is a really challenging problem. And I think all the data points to us having just this exceptional drug that's positioned to move through development, and we think make a very deep and meaningful impact on a lot of indications.

Yes, absolutely. I mean I think the selectivity is very impressive and compelling across a number of indications.

Are there any other FGFR3 selective inhibitors in development earlier stage that you're aware of? Like say this all pans out, you see this like sort of normalization and much higher growth with clean safety, this could work in many, many indications potentially. Like are there others that are earlier in development? And I guess, how hard is it to sort of make a molecule to selective?

Yes, we track this really closely. There's 2 that are early that we're familiar with, one from [ EBSCO ] and one for GeneSight, but they're both FGFR2, 3 inhibitors with some sparing of FGFR1. And if you look at the most problematic talks it's FGFR2. That's what drives the nail tox, eye tox, the stomatitis and the PPE. So I think those are going to be challenging drugs.

Our truly FGFR3 selective, we haven't seen it yet. We anticipate it. We do see lots of groups trying to find directions from our patents to move another compound forward. But I think we'll have several years of daylight between them.

Great. Well, I know we're at the top of the hour. I want to thank you guys for making the time. Certainly going to be an exciting year ahead of data from the states and including some of your early data as well.

So we're looking forward to it. And thank you guys for joining, and thanks for everyone on the line.