Hey, good afternoon, everyone. Thanks for joining the OpCo conference. I'm Matt Biegler. I'm the covering analyst for Tyra, which is the next fireside we're going to do. One of my favorite management teams. We've got Todd Harris. Todd, thanks for joining.
Thanks, Matt.
I guess we'll probably start off with TYRA-300 because it's what everyone wants to talk about. I do want to save a little bit of time. Maybe at the end, we can talk about the pipeline and kind of your core capabilities because I do think, you know, that's also pretty cool. TYRA-300, FGFR3, pretty prevalent in urothelial cancers. You're focusing on late-line metastatic and earlier-line NMIBC. Honestly, like I thought the data that put out last fall at ENA was exactly what we'd hoped for. It's a better drug, more selective drug. What are some of the maybe the pushbacks that you're still getting from people that are on the fence about the story?
Yeah, thanks, Matt. Look, we also couldn't have been more pleased with the data as we see it that we shared in the fall. This was really always about validating the very, very hard problem that Tyra took on to try and create an FGFR3 selective inhibitor and what that could do, and the high points are really better efficacy than monotherapy efficacy in this late-line, hard-to-treat population, you know, across the board than others have shown, and I think it's important to even highlight, you know, even monotherapy EV, which is standard of care first-line, didn't put up a confirmed ORR rate at the level that we did, nor did erdafitinib. Really, no one's been able to see that level of efficacy, and part of that is just this is an older, hard patient population to treat.
Despite all of that, what we were able to do is highlight on the key issues of FGFR2-related tox and FGFR1-related tox and even FGFR4-related tox, a significant reduction across the board that translates to a better tolerable profile, which we think will ultimately significantly improve patient care while hitting the target very meaningfully to put up confirmed ORR rate in the 90-mg or bigger dose of 54.5%, which is exceptional. That reads through to say we have a really selective, well-tolerated drug, which is the thesis for success and long-term success in the earlier stage disease, including intermediate-risk non-muscle-invasive bladder cancer and across a huge swath of opportunities in skeletal dysplasias. So yeah, the data is exactly what we would hope for. You asked about contentions. I know there was some concern around asymptomatic, largely low-grade ALT/AST increases.
One of the things we highlighted after the fact was that these are consistent not only with erdafitinib, but the pan-FGFR inhibitors, with ROS inhibitors, EGFR inhibitors, TRK inhibitors. Just about any TKI profile you look at in a late-line patient population, you tend to see this. Very importantly, when we do the cut of the population at 60 mg or below, and these are the two doses we're testing in NMIBC are 50 and 60 mg. The highest dose we're treating in kids is an adult equivalent of 40 mg. When we look at the 20 patients treated there, there was only one low-grade, grade 1 ALT increase. It was actually in a patient whose highest ALT level was measured at baseline before they went on drug. That was at a 60-milligram dose.
And so what we're seeing is that the relevant doses. This is, you know, and what we're letting people know, you know. This fits the profile of statin-like for an NMIBC drug and a really exceptional profile for ACH. And I think that's been a lot of the discussion. I think investors are starting to understand that. And I'd say that, you know, there's a recent Loxo abstract that came out this week that I would say really reinforces just how hard what we accomplished is, given how differentiated we look relative to anyone else that's put up data in this space.
Yeah, you want to talk about that Loxo abstract now that we've had it? It just got, I guess, unveiled Monday at ASCO GU.
Yeah. You know, this is the one question we always get on competitive pressure because really no one's made an FGFR3 selective drug before. And right behind us was, of course, LOXO and Lilly. And they're a formidable competitor, as you can imagine. We certainly applaud anyone who's doing development in this space and having options for patients is, you know, super important. Top line, you know, that data in an abstract, we're going to see the details on Friday. We look forward to that. But I think, you know, what we anticipated from their preclinical data has sort of panned out in that they need a really large exposure burden so that they're, you know, versus our 90-milligram dose, they're treating up to 400 mg twice a day. So nearly 10x the amount of drug exposure to get to the efficacy they wanted to see.
Their efficacy is actually in line with erdafitinib, you know, 42% unconfirmed ORR, 30% confirmed ORR in the abstract, and then they have a really high rate of diarrhea, and I think that probably is connected to having to take so much drug twice a day.
Is that also related to FGFR4 talks, do you think?
You know, I think it remains to be seen. We're not surprised by diarrhea showing up if you have to take a lot of drug twice a day.
Got it. So I think some of the pushback that I get, at least if we just think about metastatic urothelial, we'll get into NMIBC later. We'll get into achondroplasia later. But just with metastatic urothelial, maybe the market's not that huge, right? Erdafitinib's not really selling very well. But maybe a counter to that is that erdafitinib's a pretty toxic drug, right? I mean, like 60% dose reduction, something like 15% discontinuation. Honestly, it looks to me like on a PARP kind of level, which are really toxic drugs. So what are your thoughts on maybe how big the market is and the liabilities of erdafitinib that you're going to improve on?
Yeah, there's a really interesting, you know, poster that just came out that's going to be shared at ASCO GU on Friday highlighting that for, you know, FGFR-driven disease. I think as much as 83% of physicians say they would want to use erda, you know, post Padsev PD-1. The issue is that when you use this erdafitinib, you have this big level of dose reductions and discontinuations. One of the things we've really tried to educate the market on is that you can evaluate the erdafitinib label and see what actually drives that. The number one driver of dose reductions is nail disorders. It happens in more than one in four patients that they have to dose reduce. The nail disorders happen in 70% of patients. Next to that, in one in five patients are these mouth sores, followed by eyetox, followed by PPE.
Those top four reasons are FGFR2-driven toxicities, which we significantly reduced, as you can see from our 90-mg IC90 profile and what we shared in the fall. It's a massive reduction on what really matters and what's been hard to tolerate with erdafitinib. That's a huge win in terms of why this has been hard to prescribe. Even more importantly, those were the reasons why erdafitinib was not ultimately successful as an oral in the much larger NMIBC market. Largely a driver for why J&J put that into a pretzel to try and get local delivery. The ability to go into that intermediate-risk NMIBC market with a well-tolerated oral, you know, is absolutely preferred. It's the preferred modality for patients and even urologists.
You know, as I think we're talking a lot about sort of the economic motivations of urologists and the practice dynamics and how they're shifting towards oral drugs when they can give them, is preferred by the urologists as well.
Yeah, let's talk a little bit more, then we'll shift to NMIBC. So it's a much bigger opportunity. Incidence-wise, it's weird to me. It seems like FGFR3 is mutated in almost like three times as many patients. Why is it that patients start out with higher degrees of FGFR3 and then as you go down the lines, it becomes less and less?
Yeah, you know, that's been a question for a long time. I don't know that there's a definitive answer, but I'll reframe the question, I think, in a way that I think is important. We know that an FGFR3 activating mutation that shows up in intermediate-risk NMIBC, it's the same as the ones that show up in the metastatic. And that mutation is sufficient to cause a low-grade lesion and likely not sufficient then to drive metastasis because you just don't see that progression with these mutations. So there's some additional carrier mutations that are likely required to cause, you know, a tumor to ultimately be metastatic in addition to the growth driver of FGFR3. And so I think there's a selection bias. It's enough to cause the intermediate-risk NMIBC. It's not enough to drive metastasis. So you see it potentially less frequently and you need some co-mutations.
Necessary, but not sufficient.
Yeah.
It's competitive, NMIBC, like arguably more competitive than metastatic, right? So you've got intravesical option, CG, J&J's Balversa which you've mentioned. How do you think an oral competes there?
Yeah, this has been, I think this is a real opportunity for us to educate the market in ways that I don't think everyone understands. First off, again, more options for patients are great. And we certainly applaud the effort of UroGen, CG Oncology, J&J to come up with these intravesical options that might improve upon standard of care, which is surgical removal often requiring anesthesia and tying up an operating room and leading to, yeah, occasional emergency room visits when you nick the bladder and other complications that patients don't love, especially getting left with chemo in their bladder at the end of all this. So we applaud the effort. And I think procedures are going to get used and tried.
But I think the really important thing to highlight here is that the shift towards oral therapy, and you can track how this played out in the prostate cancer space, is a very attractive shift for patients and ultimately has been for the urologists. And what you've seen is many, if not most, of the community urology practices now set up in-office dispensed pharmacy in partnership with UroGPO. That is meaningful because it allows them to maintain these patients. There is an economic benefit for prescribing these drugs as the licensed pharmacist and dispensed pharmacy. And, you know, ultimately, that's encouraging urologists to use oral drugs in the prostate cancer space. And I think it'll encourage them to also think about its use in the bladder cancer space, especially when that is the optimal mode that the patient is looking for.
And that's what we hear again and again when we talk to patients. A well-tolerated targeted oral that they could take each day to reduce recurrence is a very attractive profile they're looking for.
I think the most of the intrathecal approaches will say that you're scoping every three months or so anyways. So is that kind of mantra going to change anytime soon, or does it not really need to?
Yeah, look, you know, the intravesical TURBT is a very different experience than the scope. It requires a different room. Let's be clear about that. While you can scope in the office for 90 seconds and view the tumor, as soon as you're adding other devices, you know, and machinery, the question of whether or not that can actually be done in a room or versus an operating room, I think I'll let the folks developing the procedures answer that. But TURBT cannot be done as a routine procedure in the office. The scope can be done in a routine 90-second procedure in the office. So I think it's important to distinguish the difference between that.
Got it. So in terms of validation for orals, you mentioned erdafitinib was tested before. I think the trial was, there was a cohort in a trial called THOR-2. It showed efficacy for sure. It was pretty toxic. How do your proposed doses compare to the dose in THOR-2, maybe just on an exposure level?
Yeah, you know, great work by J&J, you know, highlighting this opportunity and the responsiveness. They used a dose that was six mg instead of their nine milligram oncology dose. And when we look at, you know, their PK curves that are published, it's really clear that the nine milligram was sufficient to cover an IC90. Six milligram is sufficient to cover an IC50, not quite getting to the IC90. That's exactly what we see when we compare our 90 milligram dose with great efficacy and coverage of IC90 versus our 60 milligram dose, which is, well, great coverage of IC50, some patients getting confirmed PRs while on 60. So clear efficacy, but exceptional tolerability, which is why we're starting there. And 50 mg.
Our expectation as well from our preclinical data, we see a significant enrichment in the bladder over plasma, which is a typical thing you see with TKIs, which I think is consistent with what J&J saw with erdafitinib and others have seen. You have this natural bias towards accumulating drug there. I think that's why you're able to use some of these lower exposures. We're optimistic. The dose selection, we're choosing 50/60 is going to hit the efficacy tolerability profile that we want. We'll certainly explore other doses if we need to. That's really the justification of why we're starting there.
Got it. So just in terms of data this year for oncology, metastatic urothelial, you're enrolling dose expansion at 90 and 100 and NMIBC. You're starting at 50 and another cohort at 60?
We'll be randomizing between 50 and 60, up to 30 patients. You know, the THOR-2 study, I think, had a real clear signal at 18 patients at their 6 milligram dose on the efficacy, so we'll know pretty quickly. These are open-label studies. Three-month CR will be the initial endpoint we'll be able to talk about, and we'll obviously follow through with patients as we go here. First patient enrolled is anticipated next quarter on that intermediate-risk NMIBC study.
So data updates this year, probably more focused just on an update from SURF301 in the metastatic setting?
Yeah, I think the key thing, you know, you can anticipate you're learning from us this year. I think there's going to be a lot more talk around the market opportunity in NMIBC, you know, with oral. And I think there'll be, we haven't talked about achondroplasia, but obviously we'll be clearing safety cohorts there. So people question about these lower doses and any questions around safety, I actually think we can address that pretty readily this year as well. Efficacy data coming at three months on NMIBC at six months will be the first efficacy signal on achondroplasia. Those will probably time up pretty similarly. We're not committing to that by the end of the year, but certainly as we get into early next year, you know, it's going to be the timing where these things can, you can start to think about them being available.
Got it. So like that three-month, that all-important three-month CR rate and NMIBC probably shaping up early next year?
Yeah, I think, again, not giving explicit timing guidance. When we'll do that is for, you know, once we have a sufficient number enrolled, we can start to point to the timeframe by which we'll go ahead and publicly release the three-month CR endpoint on NMIBC and a six-month endpoint initially in the sentinel cohort for achondroplasia.
Makes sense. All right, let's talk about achondroplasia. You know, how are you differentiated? I mean, you know, infigratinib with Bridge, I think clearly sets the precedent here. Is the goal just with a better and more selective drug that you can really push the boundaries on what that growth velocity is?
That's really, look, the goal here is to meaningfully improve outcomes, which is not just about how much did you grow in six months or 12 months. It's about a number of important clinical sequelae. And if we take a step back and just listen to what are we learning in the patient community here around the accelerated approval that BioMarin has, you know, some patients are responding, some aren't. And, you know, when I attended the ALPE conference in Spain towards the end of last year, you know, they're starting to talk about combining vosoritide with limb lengthening surgery. And to me, that is, you know, the telltale signal that the efficacy that's desired is not there for these kids with what's being put up by the CNP.
That efficacy is, you know, in the key growth ages. They can move kids from what would be a four-centimeter baseline to a six-centimeter baseline. I think what the, you know, would really make a difference is being able to move kids, you know, far beyond that. Can we get them up to eight and a half centimeters per year? Then you start to add the element of growth that I think can really address the outcomes, the improved outcomes that you are looking for. Now, CNP, you know, has hit, has maxed out on the dose-response curve, getting kids from four to six centimeters. You can increase the dose and it does not make an impact. That is because the FGFR3 brake, which is a, you know, it is a separate mechanism from CNP, remains on.
You can't put more, you know, more CNP in the system doesn't change the ultimate outcome. And that's going to be true for a synthesis drug, BioMarin's drug. That's different for what BridgeBio's seen. BridgeBio's is just starting off on their dose response curve with their 0.25 mg/kg dose, which is really exciting, except as is, you know, really clearly articulated in the protocol they published with the New England Journal of Medicine article, as soon as they get to 0.33 mg/kg, they're expecting phosphate levels to rise. Now, that is something that our data set has absolutely and completely validated for an FGFR3 selective inhibitor. We are getting up into IC90 inhibition of the FGFR3 target before meaningful, you know, before you even start to see phosphate change in any appreciable way.
That really highlights for us our ability to engage the FGFR3 target at the right way. The max that we want to get to is probably around an IC50. That's equivalent to our 40 mg adult dose. We just saw no impact on phosphate at that 40 mg dose. So that creates the therapeutic index that, you know, and this ability to move up the dose response curve that just isn't there with a pan FGFR inhibitor. And so we're very optimistic with the doses that we're cleared to test here that we're going to be able to meaningfully change what will initially be a surrogate endpoint, analyze growth velocity, but we hope lead to meaningful differences on the key clinical sequela, which include things like reach, proportionality, but also the back pain and surgeries that will follow individuals with this condition throughout their life.
Yeah, I think, you know, going over my notes here from Bridge, it's kind of like they're able to push the oncology about like a tenth to a sixth of the oncology dose. And you're already thinking of more like a fourth to up to a half of the oncology dose. So really pushing the boundaries here. And I think the main question for me is, as we think of CNP and we think of infigratinib and we say, okay, efficacy-wise, they're kind of similar. Is that two centimeters to go from six cm, you know, annualized to 8.5? I mean, this is above 8.5. That's above kind of like the physiological range. So what evidence exists to suggest that that's safe to kind of push it that high?
Yeah, look, there's two pieces of evidence we'll highlight. One is 8.5 is what you're going to get in a year if you go on growth hormone for individuals with achondroplasia, and that was deemed safe. The issue is that that activity wanes after a year and the ultimate final height has no benefit or benefit on the clinical sequelae is nil because it's been studied for a long term. More importantly, we're really encouraged by BioMarin's data in short stature conditions that are not driven by FGFR3, that are driven by maybe a CNP receptor alteration or another idiopathic alteration where they're showing that they can get kids very safely up to 8.5 centimeters per year, and that is a really, really encouraging outcome, especially if it persists. One, because it's a safe amount of growth, but two, you know, many of these kids are either starting treatment later.
So there's some real catch-up they're hoping to achieve to address the clinical sequela. Or maybe they started on vosoritide early, but they're not getting to, you know, especially in the younger years, what a physiologic growth would be. So there's going to be catch-up in that scenario as well. So in any case here, if you can move for the period of time you're on treatment, you know, to the higher, you know, sort of normal growth curve, that's going to be accepted. And of course, there's kids that grow well above 8.5 centimeters per year in any given period of time that are on the high end of the growth chart. It's not an unphysiologic amount of growth.
We're talking about trying to give, you know, potential therapy that can be used in a way to really meaningfully change the long-term outcomes, avoid limb lengthening surgery or other things that these, you know, groups or individuals are still thinking about.
Yeah. What'd you make of some of the recent BioMarin data showing that Voxzogo can help kids that are older as well, like, you know, prepubescent, 10 years old plus still having nice degrees of efficacy? Does that read through positively to you, I think?
Yeah. I mean, look, this is, you know, you're looking to make any impact you can while the growth plates are open, right? This is a condition that's associated with stunting that growth plate. So while it's open, you want to give the best therapy to have the most meaningful impact in the time that you have. So any benefits you can show there are great. And being able to have an FGFR3 selective that hits the target directly without the off-target effects limiting it, you know, is going to be, we think, the best in class opportunity here for a drug.
But looking beyond ACH, I mean, obviously your FGFR3 inhibitor is not going to work in like short stature syndrome, but there are other opportunities and kind of, you know, hypochondroplasia kind of scenarios. How much bigger do you think those markets are for you?
Yeah. Hypochondroplasia, you know, it's another great opportunity. This is more about just height than it is other clinical sequela, which can be less severe. And that's, you know, almost a similarly sized market as achondroplasia. You know, look, BioMarin's done great on their sales, only penetrating, you know, a fraction of the achondroplasia market. You know, I think they're getting close to a run rate up, you know, nearing $1 billion. That highlights that in this one condition with, you know, 3,000 kids with open growth plates in the U.S. alone, plus, you know, a really global interest that there's a real market. Once you look at sort of hypochondroplasia, you know, potentially nearly doubling that, but then looking at a condition like SHOX mutations, that's 10 times as many kids. And it's a different condition, but it's FGFR3 related because the transcription factor directly involves FGFR3 expression.
And while growth hormone is approved here, if you talk to endocrinologists, what they'll tell you is, yeah, we give growth hormone, it might work for a year and a half, and then the kids and the families are left wanting because its activity completely wanes, which is consistent with how growth hormone works. It tends to accelerate growth plate closure and not lead to final adult height benefit. So in a generic market, it actually creates a great opportunity for us to start our development, you know, coming out of what would be maybe a growth hormone failure in a very large patient population looking for some added benefit while growth plates are open.
That really accelerates the size and interest of growth accelerating therapies that can actually work over multiple years with an FGFR3 being the actual target in, you know, what you're talking about now at 40,000 kids with open growth plates in the U.S., much broader across other markets. So this is going to be really, really exciting, you know, and it's differentiated over what growth hormone was ever able to achieve because there's really no final adult height benefit accomplished outside of growth hormone deficiency.
Makes sense. I've got two minutes. You've got two other programs. You want to maybe just summarize, I know, high level, kind of like the mojo of the company to me. It just seems like BetterMedChem, experts in crystallography, really just like the old school way of drug development, none of this fancy AI crap. What are the other two programs and kind of like what should we expect from them? And if you have time, maybe you could just from a high level tell the story of TYRA-430 because I thought it was kind of interesting how you discovered that target and FGF19+ .
You bet. I mean, the mojo of the company, yes, is we make all our drugs from scratch. It's structure-based drug design, but a real focus on FGFR biology and the FGFR protein, which is a very nuanced and hard to tackle issue. That led us to a really, really novel insight on FGF19-driven hepatocellular carcinoma, where about one third of HCC is driven by FGF19. And the efforts to date have been attempting to go after this with an FGFR4 selective inhibitor. What we realized as we did our biological work is that FGFR3 is equally expressed as FGFR4 in hepatocytes and in hepatocellular carcinoma. And it was a key bypass for FGF19 to signal through when these FGFR4 selective inhibitors were tried.
We made an extremely novel drug, TYRA-430, that is biased to inhibit FGFR3 and 4 and then spare FGFR1 and 2 to get all of that tolerability benefit so that we could tackle FGF19-driven HCC. That's actually a study that's going to kick off this year. We're really excited about it.
Yeah, that's some cool biology. I always like when companies push the science. So I appreciate you guys doing that. And yeah, looking forward to keep covering you. It's always exciting stuff what you guys are doing. I appreciate the time, Todd.
Yeah, thank you, Matt.
Thanks everyone.