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 on achondroplasia. Joining us from Tyra is Todd Harris, CEO, Alan Fuhrman, 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 companies 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 email 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. Hello everyone. Tyra is a company with a focus on structure-based drug design in 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. We've shared phase one data in a late line cancer population that highlights the potential of this approach, which is reducing some of the toxicity associated with FGFR1, FGFR 2, and FGFR 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, you know, there's nearly four.
We're losing you a little bit, Todd.
Okay. W ait, you're back.
You're back. It was the speed of the Internet, but I think we can hear you now.
Yeah.
Yep. Largely in the intermediate risk setting for NMIBC. On the skeletal conditions or skeletal dysplasias 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 + kids in the U.S. alone with open growth plates that have an FGFR3 related condition. Some very large opportunities with a highly selective molecule, TYRA-300 plus other programs in oncology, including TYRA-204. 30.
Great. A lot to discuss. Maybe starting with TYRA-300, how does your FGFR3 inhibitor mechanism compare to CNP in addressing the disease biology in achondroplasia?
Achondroplasia is a condition that's driven by a mutation in FGFR3. It's known that that mutation directly causes overexpression or overactivation of that gene. 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 brake on chondrogenesis. When it's overexpressed, it essentially stunts the normal process of physiologic growth. By modulating it 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 sequelae and growth parameters. There's really strong genetic, preclinical, and now 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 ft 3 if you're a male versus 5 ft 9.
There's also conditions of FGFR3 mutations that are essentially a knockout phenotype, a syndrome called CATSHL, for example. In that situation, males are going to grow 6 ft 5 or about 10% taller. That's because it establishes the genetic role of FGFR3 from an overactivation or underactivation 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. We actually have really good clinical data as well that highlights the effect of FGFR3 inhibition at very strong doses.
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 cm per year on average versus the 7.6 cm on average you'd see in a typical phenotype. That's driven or inclusive of complications of overgrowth. Full suppression of FGFR3 can drive really rapid growth, but it can actually drive growth too far. When we look across all of this evidence and all of these parameters, it's really clear FGFR3 is a master switch, is a really meaningful target. With 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.
Yeah, that makes sense. I think that oncology data on the overgrowth is an interesting data point that people don't talk about enough, because it's like, I mean, we should talk about what the growth is and at what point you're achieving normal and are we there yet with some of the compounds or not, how much further there is to go. I think it's an important proof of concept for the fact that a lot more growth is possible through this mechanism. We've seen that in the clinic in oncology. Let's talk about FGFR3 selectivity and why this is important and how you use this to inform the therapeutic window.
Yeah. FGFR3 selectivity is important because FGFRs, there's a family of four, FGFR1, FGFR 2, FGFR 3, and FGFR 4, and all of the FGFRs have a really important physiologic function. With FGFR1, it's a regulator of phosphate, among other things, in the kidneys. FGFR2 plays a pretty important role in the growth of nails and some of the salivary glands, lacrimal glands. As a result, what we saw initially with the pan-FGFR inhibitors that hit both FGFR1, FGFR 2, and FGFR 3 is that when you get the doses up to full engagement, simultaneous engagement of FGFR 1, FGFR 2, and FGFR 3, you see phosphate levels rise in 80%+ of patients. You see 60%+ of patients getting really problematic nail issues where their nails are falling off, mouth sores, eye tox, and PPE. Making an FGFR3 selective inhibitor is actually 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. A small molecule selective FGFR3 inhibitor is really something that no one's had done before. TYRA-300 was really the first to make it in the clinic. It was the first to be designed that way, and it has, I think, a really important place as a result.
When we hosted BridgeBio last week, they pointed to the fact that the trade-off might be, okay, maybe you have less selectivity for FGFR1, FGFR 2, and FGFR 4, but maybe you hit other components such as split four. Can you talk about the profile here?
Yeah, I think that con is driven by a lack of understanding of the structure of the FGFR family. The homology is really close between FGFR 1, FGFR 2, FGFR 3, and making a selective molecule that separates from FGFR 2 and FGFR 1 is a very, very challenging problem. Flip 4 is a kinase that you often see with a lot of, it's inhibited by a lot of kinase inhibitors with drugs like sulfur catenin, 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.
We think this hit on a KINOMEscan, much like many molecules that you see, it's important to follow up and demonstrate 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. TYRA-300 retains an exceptional selectivity profile. 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. That's something where we now have a very strong body of clinical data. With 100 plus patients now treated with TYRA-300, 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.
I'd say this is a very validated approach now with TYRA-300 that we've proven with our initial phase one data.
Yeah. Can you compare TYRA-300 selectivity and the potency for FGFR3 like relative to other FGFR inhibitors such as BridgeBio's, but also maybe some of like the other attempts in the past to target FGFR3?
Yeah, and we ran an experiment that we published in our corporate deck. It's a very clear one where we, and this is actually run by an external vendor, we leverage BAF3 cells. This is a cellular experiment that are driven either by FGFR1, FGFR2, FGFR3, or FGFR4. We actually did it head to head against infigratinib and the three approved pan-FGFR inhibitors at the time: futibatinib, pemigatinib, Erdafitinib. What we show there is nearly identical activity between FGFR1, FGFR2, and FGFR3 for the pan-FGFR inhibitors. With TYRA-300, we have high potency for FGFR3 and more than an order of magnitude separation in that cellular activity for FGFR3 versus FGFR2, FGFR3 versus FGFR1, and FGFR3 versus FGFR4. That really is the key preclinical evidence for us that we leverage, followed up, of course, by preclinical in vivo models and now clinical data.
Yeah, interesting. Okay, yeah, I see that in your deck. That's compelling in terms of the selectivity. In terms of the disease, can we talk about what this means from a therapeutic window perspective? What is the ultimate goal for what in achondroplasia? Like the amount of growth we should be looking for?
Yeah, so what we already talked about or articulated is that full suppression of FGFR3 can drive a level of growth in kids that is, you know, 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 Voxzogo. In kids that don't have an FGFR3 alteration, you can see kids growing at 8 cm, 8.5 cm per year very safely. That's a great target that we just haven't seen yet in achondroplasia. All of the agents, whether it's TransCon, CNP, Voxzogo, or BridgeBio, have been able to get kids to about 6 cm per year in terms of annualized height velocity from a baseline of about 4.
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, we don't want to get to 6 cm a year. We want to get to 8- 9 cm.
Yeah, there's ample evidence that's a safe amount. There's ample evidence that with FGFR3 inhibition you can push it, quite frankly, at. If you go too high of a dose, you would likely push it well beyond that. We want to, obviously in our phase two, dial the right dose that optimizes a target that's in line with about 8 - 8.5 cm per year.
Right. We know the mechanism can get you to that growth of 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, Ben and Acon, 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?
Yeah. I think what excites, and when we talk to the community, when we talk to parents of kids with achondroplasia, physicians that treat them, when they see the profile of TYRA-300 and then they see the result in some of the achondroplasia, hypochondroplasia, 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 of 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 this as well. All of that's seen in these very robust preclinical models, which is, I think, the most exciting part for the community of what an FGFR3 inhibitor should be able to do.
Can you maybe talk about how your, I mean, I know it's hard to compare preclinical data, but just how your preclinical data on growth and maybe any other comorbidities like the foramen magnum might compare, say, to infigratinib or even Voxzogo and TransCon CNP.
Yeah, 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 in the same lab, the studies with the two. 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 the therapeutic index to get really superiority across all of the metrics. Now, 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.
You can see that in that model, consistently we see at the dose that we've tested, this is a dose that we can achieve in the clinic and that we anticipate being able to demonstrate superior outcomes. The cross shop comparisons are challenging. You need to understand can you hit that dose. One of the things we tried to articulate is at the dose where we've shown our data in the achondroplasia models, this is a level of exposure that we saw with our 40 mg adult dose. At that 40 mg adult dose, we saw no hyperphosphatemia, no AST, ALT increases and quite frankly a pretty pristine safety profile. That's what gives us the most encouragement here, an exposure with superior outcomes in a preclinical model that we've now given multiple individuals at that same level of dose, adults, and seeing really an exceptional AE profile.
That's the therapeutic index that you would hope for with an FGFR3 inhibitor.
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 elevations and like the potential for like hyperphosphatemia?
Yeah, we are really anticipating the dose we want to get up to and probably not exceed is an average inhibition of FGFR3 at around an IC50. That was something that we achieved with our 40 mg 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. 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 of FGFR1, 2, or 4 associated tox that you would likely see with the pan-FGFR inhibitor.
Are phosphate elevations an issue? I mean, like we've heard different things, right? Because apparently, like they're elevated from the growth hormones, like, you know, BridgeBio's mentioned like that. There's physician feedback that this is very manageable. What's your perspective on that?
Yeah, look, I think what I see in the data that BridgeBio shared to date, I think they have a really nice safety profile. If one child sees elevated phosphate levels, that's something you may just see in a child. One in 20 children, anyways, already have an elevated phosphate. I think the commentary that you're getting is appropriate, that the profile they're putting up looks really safe. Now to do that, of course, they're treating at a dose that's one sixth of their oncology dose. They've moved down to a level of FGFR3 inhibition that's very modest. As you move up beyond the dose they've seen, they highlight in their protocol that they publish at the New England Journal of Medicine that as soon as they get to 0.3 - 0.4 mg they see evidence of elevated phosphate.
They know they're going to be tipping up phosphate levels quite a bit further if they go above their current dose. The level that they're seeing, I think, is very acceptable. I think they've minimized it and done so intentionally. Similarly, we anticipate we will very meaningfully minimize it by going to about half the oncology dose just simply because we didn't see it. We have that therapeutic index by designing the FGFR selectivity that I highlighted from the preclinical data.
Okay, so at the current level, it's probably manageable, but you're just able to dose higher and hit FGFR3 more. Understood?
Yep.
Can you give us an overview of your, you know, clinical trial plans in achondroplasia and the trial designs?
Yeah, let me hand that over to Doug Warner, our CMO.
Yeah, absolutely. Our BEACH301 study consists of two components. The first component is the sentinel safety cohort that's enrolling patients age 5 to 10. It involves four ascending dose levels from 0.125 mg up to 0.5 mg. Three children are dosed at each level. Once it clears the safety, the dose is increased. The primary objective of that, of course, is to look at safety. The second component of the trial is enrolling patients age 3 to 10 that first are enrolled in a natural history lead-in for six months and then are either enrolled in one of two cohorts. One cohort is naïve patients, and the other cohort is patients who've received prior growth accelerating treatment. That as well is dosing at four dose levels, 0.125 mg to 0.5 mg. Once a dose level clears in the sentinel, that dose level can be enrolled in that second cohort, one or two.
Where are you in enrollment?
Right now we have trial sites open. We haven't enrolled a patient yet, but we did see some challenges with the protocol structure. Tom, I don't know if you want me to elaborate on that, or.
Yeah, I'm happy to go a little bit further. Yeah. Ellie, we are now in, I think, a really good spot, open for enrollment, three 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 a study. We did want to make some protocol modifications so that we could allow families that were 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, were in that position. Made some meaningful adjustments earlier this year to make this really a much less burdensome protocol in families. 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 three 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, kicking this off, I think, quite successfully here.
Okay, sorry, just to clarify, when do you expect to dose the first patient?
We've guided second half of the year. We are actively, I think, in this, in a stage where we anticipate we can be both dosing and enrolling into Cohort 1 and 2 in second half of the year, which we're in.
I recognize it's a lot easier to judge from my seat behind a computer and not actually running a company or trials. Maybe can you just elaborate on some of the hurdles that you face in the site setup or initial patient enrollment?
Yeah, I think the first thing that, 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 end, especially with kids in school or going to summer school or summer camp. To do that, we needed to just decrease some of the visits required. We heard this from regulators as well as ethics bodies as we went out the gate at the beginning of the year with the protocol that we had. 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 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 tried Voxzogo or been on other therapies wanting to get on the study. We also had our Cohort 1 and 2 that Doug mentioned, but also made modifications that have now allowed for potential families to even enroll in the sentinel safety cohort if they had a prior treatment. I think those 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.
Yeah, I'm a little surprised because, I mean, I don't know if I had open growth plates, I would want the opportunity to be taller. That might just be me personally. Okay. All right.
Yeah, the enthusiasm's really strong, Ellie. We're seeing it. I think obviously the other challenge is just getting some of these academic medical centers open that can take nine to 12 months after an IND. That's where a lot of these families are really used to going, you know, so those are some of the next ones to come online that we think will really make it a lot more convenient for some of these families to be on the study.
Okay, I want to ask more questions on this study, but I did also want to ask. When we hosted BioMarin on this, they mentioned 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 non-exclusive collaborations, partnerships, just big picture, what your strategy is.
Yeah, look, we've maintained an active dialogue with all companies and ton of respect for BioMarin and what they've done here in really carving the path for treatment in achondroplasia. I think they've done an amazing job so far commercializing that, and we see the enthusiasm in the parents of having finally an option. 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 for BridgeBio success as well in this space. I think having options for these kids is great. We see that when we interact with the 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, of moving not just from 4 cm to 6 cm, but then 6 cm to 8 cm and what that means for the other clinical sequelae. 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, what do you think of the combo between CNP and FGFR3? Do you get enough growth from FGFR3? Would that be additive in terms of a mechanism perspective?
Yeah, I mean, I think our view here, and this is informed preclinically, like if we just look, for example, at our wild type models, you know, just with FGFR3 alone, if you give full FGFR, a full oncology dose and you get an IC90 inhibition of FGFR3, you're going to push overgrowth. I'm not sure the combination really makes sense in very many indications. There could be some and I, you know, love to see the scientific rationale. For FGFR3-driven conditions and then just for an idiopathic, you know, 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.
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 CNP receptor issue, then, you know, CNP is your right choice. You know, just like for achondroplasia and hypochondroplasia, I think an FGFR3 inhibitor is ultimately going to be the right choice to optimize the outcome. For idiopathic, 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. From that perspective, it might be the choice between oral and injectable. I anticipate it likely is going to work in both in the idiopathic space. Shocks, I'm not sure. The preclinical data isn't there.
We know that it's FGFR3-driven, so it should work, respond very well to an FGFR3 inhibitor. LCNPs perform there. I think we're going to have to see the clinical data first.
Okay. No, I think that makes sense. Maybe the combo, and this is my interpretation, but maybe the combo isn't more as much an achon hypocon, but maybe as we think about these much broader indications like ISS. I mean, I know right now most people are focused on achon, but my view is three 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, could perhaps play a role. I think that's interesting. Sorry, I got us a little sidetracked. I did want to ask more about BEACH301. What are we going to learn? In the second half, you're going to dose the first patient, hopefully 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?
Yeah, I think based off of where we're at today, our confidence is growing around some of the, at least the initial timelines 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, you know, be able to start to talk about efficacy, which would be kind of initially that six month annualized height velocity. This is 12 kids now. There's three children at each dose level. We anticipate that the majority of these kids are going to get a level of FGFR3 engagement that's not achieved with the dose that certainly are currently being used with BridgeBio with infigratinib. That should mean that a relatively large number of kids would have annualized height velocities that we anticipate to be superior or outperform the initial data sets put up by others at six months.
We think that could be a really meaningful data set. Of course, we've got our cohorts one and two that will fill that out. As we see that enrollment play out, I think we can guide a little bit more to when the timelines for six and then 12 month data would be there.
Yeah, cohort two is going to be really interesting because you're getting patients that presumably were on Voxzogo now.
That's right, yeah. Okay. We run an opt-in forum where patients are learning about our studies, coming on to a BEACH301 trial website and reaching out. What's been surprising is we've tracked the background. It's nearly half kids interested in the study have, the families have tried a prior treatment before. There's a strong interest and we're leaning into that now that the development's likely going to be in this prior treatment landscape, and I think with the penetration Voxzogo's already seen, that makes sense. Being able to demonstrate high quality data in kids that have been on Voxzogo before, we think is going to be super important.
The safety update in the first half next year, will we get annualized height velocity data or too early?
No, I think that initial data would more likely be the second half of the year.
Okay. We'll presumably get some safety updates throughout. Commentary on, okay, which, okay. In terms of the read through from the BridgeBio study, which I think at least for your stock, I think is a massive catalyst coming up early next year. What would be almost the best case scenario in terms of what you think it means for your clinical program and what we would see in that phase 3 data set?
Yeah, look, as I mentioned, rooting for BridgeBio success on behalf of the community that I think is excited about it, kids and getting a benefit. I mean we've all seen the Phase II data. You know, my sort of interpretation or view is that they have a great shot at getting an annualized height velocity of about 6 cm 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. 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. I think that'll pay for a lot of enthusiasm around further target engagement with an FGFR3 selective compound.
You expect to see around like 6 cm or so of growth, but you think that we should be really looking for like 8 to 9 ultimately long term?
Yeah, I think with BridgeBio, expect to get 6 cm would be the expectation from the data we've seen. Yeah, getting to, you know, getting to eight, eight and a half really provides a great opportunity, I think, to make more meaningful changes on the other clinical sequela while the growth plates 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 they've shared publicly, this looks like a well-tolerated drug at the 0.25 mg per kg dose, 1/6th of the oncology dose. Their level of target engagement is relatively modest for all of the FGFR1, FGFR2, and FGFR3. Lack of clear safety signals is not too surprising. Obviously, you see a more modest growth as a result of being at that low dose.
Makes sense. Just in terms of the timelines for TYRA-300 and the cadence of what we can expect to learn, can you be a little bit more specific on what we'll be able to learn around the safety from the sentinel cohort at this update in the first half of next year? What info on safety you'll get, basically?
Yeah, again I think 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's drug related or not. I think in the BridgeBio data, they had some diarrhea but it wasn't like a dose response across their low to high dose. They had one elevated phosphate I think in their safety data set, but it wasn't even at the highest dose, which to me makes me think that probably not a concern. That'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.
Yeah, similar profile for us as others have seen I think would be a huge success. Of course differentiate on efficacy is the goal.
What are your expectations from a growth perspective when we ultimately get that, from both Cohort 1, the naïve patients, and Cohort 2, the ones that had been on Voxzogo, in terms of growth and what are your expectations there? Honestly, it's just based on the biology and what we've seen in the oncology setting. It would surprise me if you don't see much more meaningful and uptake in growth. Can you give us specific numbers? What do you expect to see at those dose ranges?
Yeah, I mean, I agree it would be surprising based off of the science, you know, scientific rationale here to not see something. It's really, this is all about dose optimization. What we're looking for is getting to again that 8 cm to 8.5 cm per year during the window that we're treating the 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, can you talk about kind of the much larger opportunity set where you think that like FGFR3 could play a role? Let's talk about sort of some of like the sizing of these populations from a prevalence perspective.
Yeah. I cite your work a lot, Ellie, here because I think you, you've 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, you know, that idea I think is 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 Turner's. That's 20,000 - 30,000 kids in the U.S. with 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 in just the U.S. alone. You're talking about a really significant population looking at potentially a growth accelerating therapy or a condition modifying therapy in the case of achondroplasia and hypochondroplasia. There's an expansive growth opportunity.
Baumorin I think has done a good job highlighting where they're going and why and what this looks like. One of the really interesting things, there's been a whole market that's evolved with growth hormone and the early promise there was getting children to additional benefit and final adult height. The reality is that in nearly every condition except for growth hormone deficiency, growth hormone pushes growth in the first year to 8.5 cm to 9 cm 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. You've got this whole market, I think that's been primed, but without an agent that actually delivers improvement in final adult height.
If you just translate to what we've now shown, for example in our wild type animals where if you give an oral dose of TYRA-300, you know, at the right amount, these animals may grow 8% taller, their long bones are going to grow that level of additional growth. This is kind of a master switch to push growth when you need it. I think that evidence gives us a really strong encouragement that the market that 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? Also, do you need to have FGFR3 selectivity if you go beyond achondroplasia and hypochondroplasia? Maybe we just start with the first of how you split it.
Yeah, let's start with the first. 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 the SHOC2 mutations because that also is a transcription factor that directly upregulates FGFR3. Now with our wild type data that we published at ENDO and in JCI, idiopathic short stature as well. Now idiopathic by definition means you don't know what's driving the lack of growth. There certainly could be some kids that might respond better to an FGFR3 inhibitor, and it's possible others might respond a little better to CNP if it ends up being a mechanistic mechanism that's downstream of CNP versus FGFR3.
Across the board we have a high degree of confidence FGFR3 will be an oral agent that could, that will be the right target to have a pretty meaningful impact across all of those.
How would you explore or think about what the dosing would be with CNP? We've seen that the dosing might even be lower in some of these other indications. How would you approach that, and how does, what's the therapeutic window in these other indications relative to achondroplasia?
Yeah, I mean this is a, you know, until you do those studies it's hard. You have to do the work, you have to do a phase two. We tried to use a really strong genetic rationale to the dose we want to go up to and I highlighted that syndrome called CATSHL, which occurs in families where one of the FGFR3 alleles is mutated, so it's nonfunctional. I think that's a good recapitulation of what it looks like to have an IC50 inhibition of FGFR3. With that syndrome, there can be some hearing loss that's thought to be related to prenatal FGFR3 suppression. The families are relatively healthy but they're growing 6 ft 5, so it's 10% taller than the average population. You can see some overgrowth in the rib cage with something called pectus excavatum. That's a good representation of what we would call the limit.
It's why we've designed up to our 40 mg adult equivalent or the 0.5 mg per 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. That's our best guess today based off of the genetic. We published doses down to half the oncology dose where we see wild type animals get statistically significant improvements in growth that I think reinforces that idea. Now looking clinically, we know kids that have gone on the pan-FGFR inhibitors at full oncology dose are getting to that 19 cm per year. That's too much.
We also know from our data that at half of our full oncology dose at around 40 mg, we have an exceptionally well tolerated drug while the growth plates are closed. Moving that type of dose into children with open growth plates we think gives us the best chance at pushing, exploring the limits of growth acceleration with the selective inhibitor we have.
Great, yeah, really, really interesting opportunity set in terms of maybe pivoting to oncology. 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 at oncology and in particular the safety profile that's been reported? This is something we get a lot of investor questions on.
Yeah, so, you know, we started in our SIRF-302 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 mg dose or above, exceptional efficacy in this population for the FGFR3 positive metastatic urothelium. We're seeing a 50%+ ORR. What was most remarkable and the key thing we really wanted to demonstrate here was the improvement on safety. We looked across metrics like hyperphosphatemia, which you would expect on a drug like infigratinib to be about 80% when you hit the oncology dose. That was all the way down into the teens. Low grade nail toxicity, which would be one in four patients would dose reduce as a result of nail tox with Erdafitinib, and it's going to occur in 60%+ patients.
I think we had 1 out of 15 patients with low grade nail disorder, same with stomatitis, 1 out of 15 patients. PPE, I think it was 2 out of 15 patients. 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 from the beginning. With that evidence, we had also done something in this study where we tested 22 patients at the lower doses, with 20 of them receiving 40 mg or 60 mg at the outset. In those patients, we had pretty much the, you know, 1 out of the 20 that had a grade 1 ALT increase was actually a patient whose highest ALT measurement was on baseline before they went on drug. No hyperphosphatemia, no dose reductions, and an exceptional 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 in achondroplasia, which would be the 40 mg adult dose, but also the dose for testing in earlier stage bladder cancer, the 60 mg dose, where again, tolerability would be really important. We have clear evidence that that's a tolerability profile that could be very acceptable for an oral targeted treatment in the intermediate risk NMIBC setting.
Yeah, I mean, I think you recently announced you dosed the first patient in the SIRF-302 study in intermediate risk NMIBC. Can you give us kind of an overview of sort of the competitive landscape there, where you think you fit, and sort of the value proposition?
Yeah. We are the only company pursuing an oral targeted therapy here. JJ had tried this with Erdafitinib a few years back, but didn't get the tolerability profile they wanted with the high rates of hypophosphatemia and the FGFR2 toxicities that I just highlighted. With that in mind, they also saw exceptional efficacy. They saw an 83% CR rate with that oral drug when they tested this population. It's clear that the patient population is highly responsive. With the selective drug, it makes a ton of sense to seek a high degree of efficacy that could be well tolerated and given for multiple years. 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; you're going to need to go under general anesthesia for the standard of care TURBT surgery.
Avoiding that could be a huge benefit. The other competition today are all looking to go after this with a procedural solution. Most of these agents were tried systemically and weren't tolerated, so they moved these into something that you can insert through the urethra, through a 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 in a gel. These are all great options for patients. It's an alternative procedure to the surgery.
If you look at the way that the prostate cancer landscape has evolved in the urologist setting, moving towards an 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 less time in the office, in the surgery room. They're able to avoid the, you know, buy and bill can be favorable in the sense they get some spread on the drug. It can also be challenging because you have to buy all this drug up front, sometimes withhold your partner's checks to do so.
An oral, there's a model now where they do in-office dispensing, 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 while continuing to support the practice economics. We think that's exactly where bladder cancer is going to go in the urologist's office with a targeted oral agent. We're the only ones in development here, and I think this will be one of our first data sets to come out. We're anticipating next year, and I think it's going to be a pretty exciting game-changing therapy for the space.
Yeah, that's really, yeah, really exciting. Maybe just can you go into a little bit more detail on the design and, you know, specifically the timelines and what we should expect to see from the initial data?
Yeah, let me have Doug handle this one too.
Sure. So yeah, we have a Phase II study that's enrolling patients with low grade intermediate risk bladder NMIBC and also having activating alterations in FGFR3. Patients are randomized into one of two arms, one arm testing 50 mg QD, the other 60 mg QD. This is a marker lesion study, meaning some of the tumors are left in, in order to evaluate response. The primary endpoint of the study is 3 month complete response, and we have secondary endpoints such as duration of response, recurrence free survival, as well as safety. As Todd mentioned, we'll have some initial 3 month CR data in the first half of next year from both of those cohorts. Great.
What should we be looking for in terms of the bar of what would be, you know, good data?
Yeah, great question. As Todd mentioned with Erda, they saw an 83% response rate, and you know, associated with severe toxicity. Given the convenience and preference of an oral therapy, when we talk to KOLs and investigators, they think 70% CR would be an effective level of activity in the oral setting.
What's good on safety? I mean it's oncology setting, but I guess what would be like good safety in that context?
Yeah, it is oncology, but if you talk to urologists, they're not exactly like your medical oncologist. They really want quite a safe, well-tolerated therapy. As Todd mentioned, at the 60 mg and below dose, we're not really seeing any significant toxicity in terms of hyperphosphatemia, AST, ALT elevation, dose reductions, that sort of thing. We anticipate a pretty clean safety profile at the doses we're evaluating.
Okay, we look forward to that update. Just going back to the safety profile in achondroplasia and growth disorders, because at least in my view it's 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. Just going back to kind of like potential for hitting, say, FGFR4, you published sort of the KINOMEscan and what we, at least what's out there, that can give us confidence we wouldn't see any other toxicities.
Yeah, we have published the KINOMEscan, we published TYRA-300 both in a peer-reviewed paper as well as we've had on our corporate deck. I think for some time in the early days. The KINOMEscan, you know, the most important thing to understand, you know, you do it, you do a KINOMEscan obviously to follow up on any targets that you want to dive into deeper. The only thing that showed up as, you know, similar potency to FGFR3 was FLT4. Next to that we started to separate very meaningfully from FGFR2, FGFR1, and any other targets where orders of magnitude separated. Follow up on FLT4 really bore no fruit.
You typically see an enzymatic activity for FLT4, like if you look at sulfatinib 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. That's not surprising because you have a very artificial assay to test all these kinases in a high throughput format. 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. This is a hit in an artificial assay that on follow up really bears no concern for us. There's really no other hit beyond the other isoforms that we've had a meaningful concern around.
We now demonstrated that separation all the way into SIRF-302 clinically, demonstrating a significant reduction on what those might cause. From our perspective, from our KINOMEscan, to our follow up in vitro assays and cells, and now to preclinical safety models and now to clinically, this appears to be an exceptionally well tolerated and selective FGFR3 inhibitor. 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 perfect translation. Even as others look at highly selective FGFR3 inhibitors that look good in a KINOMEscan or look good enzymatically, that translation also requires all 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.
Those are the kinds of things that start to create challenges. For Loxo, for example, 435 needing 400 mg twice a day and not being able to get a consistent level of exposure is just one example of the drug properties, properties that can trip up an otherwise good selective inhibitor. This is a really challenging problem. I think all the data points to us having just this exceptionally exceptional drug that's positioned to move through development, and we think make a very deep and meaningful impact on a lot of indications.
Yeah, absolutely. 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 and we see this sort of normalization and much higher growth with clean safety? This could work in many, many indications potentially. Are there others that are earlier in development? I guess how hard is it to sort of make a molecule this selective?
Yeah, we track this really closely. There's two that are early that we're familiar with, one from Abbisko and one from GeneSight, but they're both FGFR2, FGFR3 inhibitors with some sparing of FGFR1. If you look at the most problematic tox, it's FGFR2. That's what drives the nail tox, eye tox, the stomatitis and the PPE. I think those are going to be challenging drugs. A 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. I think we'll have several years of daylight between them, between us.
Great. 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 space, including some of your early data as well. We're looking forward to it. Thank you guys for joining and thanks for everyone on the line.