Everyone, if we could get the folks at the back of the room to move out of the room so we can start the next presentation with Tyra Biosciences. I'm Josh Schimmer from the Cantor Fitzgerald Biotech Equity Research team. Very pleased to welcome Todd Harris, Chief Executive Officer. Todd, maybe give us a quick snapshot of Tyra and what we should be looking for from the company over the next twelve to eighteen months.
Thank you, Josh, and hello, everyone. Happy to be here at the conference. Tyra Biosciences, we're a precision medicine company. We have a small molecule drug that targets FGFR3 as our lead drug. Came out of a homegrown pipeline. We call it the SNAP Chemistry Platform. If you come visit us in Carlsbad, you'll see where we make drugs. This lead drug is the first FGFR3 selective inhibitor to make it into the clinic. It's in a phase 1 study, oncology, all comers, but also individual FGFR3 positive metastatic urothelial cancer. We're gonna have our first data readout with that first-in-human study this fall. And the other major milestone for us with that same drug, we're gonna be targeting achondroplasia, and plan to submit a phase 2 an IND for phase 2 in achondroplasia.
FGFR3, a really meaningful target in bladder cancer. It's a driver mutation, and in skeletal dysplasias, including achondroplasia and hypochondroplasia, it acts in the growth plate. While the growth plates are open, there's a break on chondrogenesis. Same molecule, but the target has really interesting biology in both, and so we're gonna pursue in both.
Okay. Maybe you can tell us a little bit about the SNAP platform and what differentiates it versus other approaches to targeting tyrosine kinases.
Yeah. So we're, you know, we're a structure-based drug design-focused company, but what really differentiates us are the capabilities that we've built in-house. So if you were to come visit us in Carlsbad, you'd see we do crystallography on State Street in Carlsbad. We have, you know, a full team that does that, that's really, you know, has an expertise in being able to turn it around quite rapidly. And we have a lot of expertise in the FGFR family. The FGFR family has, you know, four isotype members, and the active sites are nearly identical.
And so crystallography, especially around the active site, plays a very important role in trying to make selective drugs, and it's something we've leaned in on, and it's something that we do very frequently with a very rapid turnaround, as well as, you know, your standard cell-based assays for measuring cell activity, and then we've got an in vivo team as well, with a vivarium in San Diego that we perform our in vivo. All of those activities, we focus on rapid turnarounds so that we can iterate our chemistry quickly to differentiated drug candidates.
Is the reason you started with FGFR3 because you have the expertise in FGFR, or do you have the expertise because that's where you started?
We built the capabilities... My co-founder was a structure-based drug design guru and a longtime crystallographer. We identified an opportunity and then really built the capabilities in-house to tackle this problem of how do you make an FGFR3 selective drug?
Got it. Well, maybe we can talk a little bit then about the solid tumor unmet need. What percent of patients do have FGFR3 driver mutations?
So in the late line setting, we're talking about 20% of bladder cancer patients, but when you look at bladder cancer, there's about 80,000 new patients a year in the U.S. with bladder cancer. 80% of those are going to be early-stage, non-muscle-invasive bladder cancer, and the vast majority of those are gonna be intermediate risk. It's likely not an indication that's going to you know cause death in the next five years, but it's gonna cause really a lot of morbidity. It really associated with repeat procedures, chemo instillations in the bladder, BCG instillations in the bladder. So that patient population is largely the majority, are FGFR3 positive. So it's a really big patient population in the early stage disease for a potential targeted therapy that hits FGFR3.
Got it. What type of mutations do they have? Are they translocations? Are they amplifications?
These are all activations on the oncology side that cause constitutive activation, and it happens either through a fusion, which is a you know pretty standard type of activating mutation you see across a number of different TKIs. Or what's unique to FGFR3 is you have these cysteine mutations, and they act a lot like a fusion because this is a dimerizing protein, and these cysteine mutations, this is an amino acid that swaps to a cysteine cause the cysteines to form a disulfide bridge, and then it glues the dimers together, and you get constitutive activation without ligand.
Got it. Maybe you can talk a little bit about the extent of selectivity of TYRA-300. What other kinases might you hit, and where do you expect the dose-limiting tox to be driven by?
Yeah. So we have. We built the molecule to really have an order of magnitude separation from FGFR3, when compared to FGFR2, FGFR1, and FGFR4. And the key assay we look at, you know, is this cellular assay, Ba/F3 driven cell lines, to assess that. In terms of other, you know, other targets, you know, those are the closest cousins, so those are. Is it still, you guys still getting this? Yeah. Those are the, you know, the likely other, you know, toxicities that we might see that are not FGFR3-related would probably still come from those other family members, even though they're tenfold apart, because we really don't hit anything else, meaningfully, till after that. So when we think about what's, what's gonna be driven by FGFR1, it's hyperphosphatemia. What's driven by FGFR2?
There's the diarrhea, AST, ALT increases, and that's typically linked to the FGF19 Klotho FGFR4 pathway and cholesterol homeostasis and bile acid synthesis. FGFR3, you know, to date, really the only known toxicity you see comes out of the animal models, and when you treat animals that still have open growth plates, you'll get overgrowth, and that's because FGFR3 is known to be a brake on chondrogenesis. And so it actually is a dose-limiting toxicity driver in a lot of the animal models where the growth plates are still open, is FGFR3.
Got it. We'll come back to the growth dynamic-
Yeah.
-program, but sticking with the oncology setting, maybe give us a snapshot of the clinical trial. You said data this fall. Maybe the design characteristics of the trial and what we should be looking for.
Yeah. So to try and move quickly, we designed a study in two parts, with part A really trying to find the highest dose, and that was in all comers. That was intended to really move quickly, look at initially a single-patient dose cohorts, but then a three plus three design looking for an MTD. We announced at the end of last year that we actually completed that portion, not getting to an MTD. And essentially what we saw was from a PK, another biomarker, you know, perspective, what we wanted to see and felt comfortable we didn't need to increase the dose. Then we had a part B, and the part B was focused on or has been focused on FGFR3-positive patients, and where we could, we've enriched for metastatic urothelial.
And we started to open that up at doses where we anticipated we could see some efficacy. We've done multiple cohorts, and what we've tried to do is enrich for, you know, up to about 10, where we could at sort of the right dose, right patient, and really focus on that FGFR3-positive metastatic urothelial, with the intent of identifying a dose that could potentially be efficacious.
So maybe you can talk a little bit about the benchmark products. I guess Balversa would be one to consider, you know, what that showed and where you think you need to be relative to Balversa.
Yeah. So Balversa, you know, erdafitinib, it's put up the best data in urothelial. There has been multiple pan-FGFRs that have been studied here, and erdafitinib was the only one that did continuous dosing. They've been able to get to an on-label ORR of 35%. That still means there's a decent amount of patients with clinical benefit. The real challenge, though, with that drug has been keeping patients on it or dealing with the toxicities that emerge, particularly after the first month when you get into the second month, and all those toxicities that I talked about. So it's really, you have meaningful efficacy, but tolerability, that's been the issue. So for us, as we look at that benchmark, you know, we want to... You know, we're looking to achieve an on-par efficacy to erdafitinib.
That would be the data that would convince us that we're hitting FGFR3 with an IC90. And the real concept we wanted to prove with this study is, when we get to that level, what does the FGFR1, 2, 4 tox look like, and can we really prove out this selective hypothesis of reducing those toxicities when, you know, in the face of an efficacious dose?
I thought Relay with their FGFR2 showed a meaningful increase in response rate. Is that a different dynamic, FGFR2, being able to optimize for selectivity and improve the response rate in contrast to FGFR3? Is there a chance that you think you can do the same, you can show a substantially higher response rate as well?
Yeah, I mean, it's... Look, it's different biology, and you tend to have... In FGFR2, it was very compelling to see that ORR rate go up. A lot of patients on the other drugs were seeing clinical benefit, and PFS is out to 10 months, which means, you know, even if you didn't get a response on a pan-FGFR inhibitor, you're getting a lot of benefit and a real durable treatment. With their high OR, I think it came at the potential risk of all of the on-target FGFR2 tox, and I think that data emerges, you know, a little bit later, and I think they're gonna do an update here at the Triple. But even in their last update, you can see the nail tox and the stomatitis, and all these issues start to pop up.
I think generally, you know, patients are, you know, very happy to stay on drug and have disease control without the severity of those toxicities, and when you add those toxicities, you're either gonna see dose reductions or discontinuations and, potentially put your PFS at risk. This has been a lot of the dialogue the FDA has emphasized recently around what's your, what's your optimal dose, and what's the dose that's actually gonna win on PFS? It's not always pushing a ORR signal up front when you're sacrificing tolerability. So I think the jury's still out a little bit on that data. I'm gonna be interested to see what they report out here in the next few weeks. But you know, it's a cautionary tale for us, where we're not necessarily looking just to push ORR here.
We're looking to identify a drug with really strong disease control, some evidence of on-par efficacy, you know, and really then improve the tolerability to increase the chance of a meaningful PFS signal as we develop the drug.
... I don't think J&J breaks out erdafitinib sales yet. Do we have any sense where they're tracking?
We really don't. I mean, it's, if you talk to physicians today, they'll tell you they don't like giving erdafitinib, and it's not because of the efficacy, it's because of the issues of tolerability they're gonna deal with at week six. They're gonna have to take a patient off of a drug and send them for an eye exam or the nail toxicity. They just don't know what to do with it. So then they start to think about gemcitabine or other second-line options because it just doesn't. It's not performing the way that they want, and they're, they don't feel that they're meeting the needs of their patients with a drug with that type of profile.
So I think providing a well-tolerated targeted therapy, I think, will really change the narrative for physicians and their interest in prescribing beyond what it is today.
Assuming that you hit the product profile that you're hoping to achieve, maybe we can share your thoughts on the development path, right? There's refractory, there's earlier line settings. We're even seeing erdafitinib move into J&J's pretzel technology for an NMIBC. So how do you kinda see the evolution of TYRA-300?
Yeah, look, despite them not disclosing sales in the metastatic setting, they are indicating they believe this is a $5 billion market, with erdafitinib and the TAR-210 platform probably being their flagship opportunity. That's because when you go into the early-stage disease, there's a very high prevalence of FGFR3 positivity. They actually tested, J&J tested oral erdafitinib in this setting, saw an 83% CR rate at a lower dose than they used in the metastatic setting. So there's really compelling data, you know, validating the target with an oral. The issue was, even at that lower dose of six mgs instead of eight or nine mgs, that all of the tolerability challenges were still there in terms of the nail tox, eye tox, the stomatitis.
And so they discontinued and put that into a localized pretzel platform to try and, you know, still hit the target but reduce the tolerability. So for us, we see that-