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

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 losing 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.