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

The last day of Bank of America Healthcare Conference here at Vegas. My name is Hao Shen. I'm associated with Jeff Micron, who is the Senior Biopharma Analyst at Bank of America. Today, it's my great honor to have Todd Harris, the CEO of Tyra Biosciences. Todd, welcome.

Thank you. It's nice to be here.

Maybe just to kick off the conversation, could you maybe just give a high-level view of Tyra as a company?

Yes. So Tyra Biosciences is a company focused on precision medicine. We make small molecules. We actually make them from scratch. We do structure-based drug design. And our unique approach is our SNAP chemistry platform, and it's a rapid, iterative in-house capability that we've built to make really differentiated molecules. And we largely focus this on FGFR biology. Our lead asset is TYRA-300. It's the first FGFR3 selective inhibitor to make it into the clinic, and we're in a Phase I right now. We have other assets as well behind it. We can talk about that.

Sounds good. Just to dive a little bit deeper into your SNAP platform. How would you say it's sort of differentiated from either platform or developing small molecular inhibitors?

Yes. So structure-based drug design, you're looking at structure-activity relationships. That involves crystallography or whatever approach you want to use to see how your ligand or molecule that you're designing binds the protein. Conventionally, protein crystallography is something that's done sporadically and may take several months. This is an in-house capability we built so that on the order of as little as 3 days, we can take brand-new molecules that arrive in our lab in Carlsbad and mean a full crystal structure. That allows our chemists really detailed structure information on each of the analogs of interest that we want to look at. And it's really important in FGFR biology because the FGFR isoforms 1, 2, 3 and 4, they're all important in a variety of different conditions. But when you want to hit one of them, the active sites are nearly identical in fact, are identical in the first sale of the active site, and then you have to look at more subtle changes outside of that. So we leverage crystallography across all of those isoforms with our in-house capabilities to look at detailed differences and design more selective molecules. We couple that with 2 other functions that we prioritize in-house. One is our cancer biology and cell biology group with a ton of cellular assays that give us on-target and off-target information in an in vivo group as well.

Awesome. That's very helpful. Let's dive into your lead asset, TYRA-300's kind of exciting development you had started a Phase I. But maybe let's get one step back. Could you maybe provide us an overview about TYRA-300 and how it's sort of differentiated from other FGFR inhibitors?

Yes. TYRA-300 is an FGFR3-selective drug. There are 4 approved TYRA-FGFR inhibitors that equally hit FGFR1, 2 and 3 that are on the market today. And the key here is understanding what the limitations are of a drug that hits all these isoforms versus one that might be selective. We know from the late on-label adverse events and AE tables of these approved drugs that the majority of patients on oncology doses will get hyperphosphatemia, which is driven by the FGFR1 tox. FGFR1 is in the kidney regulating phosphate. That leads to the need to monitor your blood, go on phosphate binders, and it could lead to tissue mineralization. One of the more debilitating chronic toxins comes from FGFR2 tox. And what you start to see is your fingernails will disfigure fall off, and it's incredibly painful for patients and often leads to dose reductions. There is really bad mouth smell as well. And that's because of FGFR2's activity appears in the glands, and you see that in the preclinical tox models. FGFR4 has some GI tox and liver tox as well. So if you can make an FGFR3 selective drug, of course, you could avoid those toxicities. And the opportunity for an FGFR3 because of its driver in bladder cancer and skeletal dysplasias, there's a ton of unmet need that you could address if you could design one of these molecules. So it's a very hard profile, one that TYRA-300 is really one of the first -- it is the first to make it in the clinic that achieved that, and we see a ton of promise by being able to selectively hit this target.

Okay. So I think potential safety differentiation would be one of the key [indiscernible] TYRA-300. Could you talk a little bit maybe also about -- I think you had some data showing it's also sort of works in FGFR-resistant kind of preclinical models.

Yes. Great point. So the other key limitation of those panFGFR inhibitors that are on the market today is all of them have a gatekeeper liability, and gatekeepers are mutations that happen in the back pocket of a kinase -- the active site of the kinase domain. And typically, the first resistance mutation that crops up if you have a drug that is using the back pocket for binding affinity. We've seen it in EGFR. We've seen it in RET. We've seen it in ALK. Just about every target has had this gatekeeper motif arise. And if your drug is accessed in the back pocket, it has a liability. So we designed TYRA-300 to avoid the back pocket structurally. And as a result, we have near equal potency whether or not you have this gatekeeper mutation. And it shows up in the clinic in patients with bladder cancer. The limited data that we have suggests maybe 20% to 30% will have this gatekeeper mutation. The #1 reason that patients are coming off of therapy actually tends to be the tolerability issues, though.

Makes sense. Phase I study is ongoing. Could you talk about the design of the study and just generally how it's progressing?

Yes. We designed the study in 2 parts as a Part A and a Part B. Part A is all comers. As we move up in doses, it's a 3 plus 3 design, and it's pretty standard. We're trying to get to an MTD as quickly as possible. Part B, we're looking at FGFR3-positive patients and starting to look at PD and efficacy. And we're able to, as soon as we clear a dose in Part A, move into those selected patients in Part B. And we're going to be looking at multiple doses, one to fulfil project optimist, but 2, because if FGFR3 doesn't lead to dose-limiting toxicities, which to date, we don't think it would. It may be the other FGFR isoforms, and therefore, we don't want to overdose and lead to tolerability issues when we can hit FGFR3 just as well at potentially lower doses than our MTD. So that gives us a chance to balance the efficacy safety window we think we can achieve.

Awesome. In terms of data release strategy, were you thinking maybe some interim analysis possible or maybe even more preferred to like release the mature data, which can tell us sort of the whole story?

Yes. We feel really strongly about this, that the right thing to do as a company and quite frankly, for investors is to wait for a really mature data set from our Phase Ia and Ib study because splashing out a little bit of data here or there. We just don't think it's going to tell the full story of what we're trying to achieve with this study. And so we haven't given guidance to date on when we anticipate the full data set being available, but we have let folks know we're going to wait for the data to mature. I think one caveat to that is, and we'll talk about achondroplasia. That's an area where we anticipate the dose being lower, which means we start to see a lot of that data on the Phase I portion pretty quickly. And the oncology data is not really as relevant there because it's more of a lower dose PK exposure. We think that's going to be relevant. So certainly, that's information that's helping us with the design and planning prior [indiscernible] study, which you plan to kick off next year.

Awesome. Let's jump to the A counterplayer plan. So you guys expanded TYRA-300 to contemplate this year. Your competitors have shown promising data self-service proof demonstration of the FGFR inhibitor in these indications. Could you talk a little bit about your sort of sort of expanding the TYRA-300 to a counterplayer and how it's differentiated from other competitors, FGFR inhibitors?

You bet. First off, I want to come in companies like BioMarin and BridgeBio and the patients and investigators that have done those studies because it's been a really exciting few years for kids with achondroplasia, starting with the BioMarin approval. I think the data there highlighted that there's some benefit in terms of the surrogate of annualized height velocity, and kids and their parents are starting to see that benefit in the market today. What was exciting about BridgeBio's recent data is I think their cohort 5 really gave this indication that the headroom or the kind of max benefit VOXZOGO was getting to that we can actually do better. And it started to hint that by just direct FGFR3 inhibition. You might actually get to average height velocity in kids with this condition. Kids with achondroplasia from age 2 to 10, they grow 4 centimeters per year. Kids without achondroplasia are growing, on average, 7.6 centimeters per year. So this is a big gap, and it wasn't necessarily thought that you might close the gap from the BioMarin data. BridgeBio didn't close the gap either, but it's showing that with FGFR3 inhibition, they're kind of on the dose-response curve you could get there. Now BridgeBio decided to not dose above Cohort 5 from their public disclosures, and that makes sense because they are a pan FGFR inhibitor. So you do have FGFR1 and 2 getting it inhibited at the same time and at the same level when you're inhibiting FGFR3 in the active growth place. TYRA-300 has this opportunity to fully inhibit FGFR3, not necessarily full 90%, 95%, but the way that you want to restore the tone to potentially normalize growth and to do so with a nice separation from FGFR1 and 2 and potentially a nice therapeutic index to explore the right dose for these kids. And that's what we're excited about taking TYRA-300 into a Phase II next year because we're going to have this ability to look at multiple doses to really optimize the outcomes.

That's very exciting. Just wanted to dive a little bit deep into your dose selection. You mentioned that probably different from oncology applications, and you have Phase I in oncology trials. How are you seeing all the information that you will be able to get to sort of guide your Phase II dose for the achondroplasia trial?

Yes. We do a ton of work preclinically to look at this. We're getting as much information as we can. And I think the story that's emerging is pretty clear. You can start with the data from BridgeBio, where they showed -- they're about 1/7 of the oncology dose where they're starting to see some good responses in 10 kids, a small numbers, but really, that's still a pretty big gap between kind of full inhibition or at least the oncology dose. It highlights that we're likely not going to dose up in oncology just with TYRA-300. You don't need to. And the right area to be exploring in dose is going to be somewhere below. We think no more than half the oncology dose likely. So when you think about this window from 1/7 up, there's going to be a level there that I think is appropriate, and it's going to be lower than the oncology dose.

That makes sense. Just to kind of follow up on that. So your Phase II study, you plan to start next year. What needs to happen between now and next year for that to kind of kick-off?

Yes. Pretty straightforward set of exercises we're undertaking. We need to finish our kid-friendly formulation. And there's some important regulatory requirements we need to talk to the FDA about those. But some of them are standard guidance they've given, making sure that we do a juvenile tox study and then making sure that we have the chronic dosing out beyond the 13-week studies that we've done. So that's a 6 and 9 months. Those are things that we need to have ready and in line for chronic dosing in kids. We're working very thoughtfully and aggressively towards ensuring that we have all those complete as well as obviously preparing to talk to the FDA and make sure that we have all the right guidance from them to make a good study.

You mentioned about kid-friendly formulation. Could you maybe add a little bit color about what needs to be done sort of to have that kids-friendly nature there?

Yes. Obviously, you go from capsules looking at tablets and then there's really unique forms from there where you can look at sprinkling and dissolving or otherwise. So we're doing all the work to make sure that we've got a great formulation that's ready. No major barriers. It's really just doing the work and choosing the right format and moving forward.

Beyond TYRA-300, TYRA does have other assets in the pipeline. So just high level-wise, what else do you feel excited about?

Well, I would be remiss not to mention how excited we are about TYRA-300 for oncology, not just because of where we think this Phase 1 deal go, which is in late-line patients, but because of the opportunities in non-muscle invasive bladder cancer. And the folks at Janssen developing erdafitinib have put up some really exciting data, and I can commend them and the patients, highlighting what FGFR3 inhibition can do. So aside from the late-line metastatic kind of 40% response rate that you see with erdafitinib, an interim data showed 68% response rate in the first line in combination with PD-1, that's in line with what's seen with EV. And then in the NMIBCG-resistant, erdafitinib showed 100% complete response rate, 9 patients. And then in intermediate risk, a 75% complete response rate. The challenge with every single one of those studies is that the toxicities are pretty consistent, and they are the pan-FGFR toxicities that we worry about with the cronies and the stomatitis and patients just having a hard time staying on drug. So most instances here, patients are staying on for a few months and then coming off. So being able to really hit FGFR3 more selectively and see the same types of outcomes in terms of initial responses, but then allow those to be durable because patients could stay on the drug and tolerate it is really the goal. And I think we'll know a lot from the Phase Ib about what the potential is here along those lines. And that will allow us to kind of move in similar directions with Phase IIs across all of those opportunities to then prove out really not just the efficacy, but then that potential durability with safety. So that's really exciting on the oncology side. TYRA-200 is uniquely positioned in Intrahepatic cholangiocarcinoma to come behind all of the approved and end-stage or in development assets by addressing the molecular breaking gatekeeper mutation. That's what's shown up at month 10 in these patients, and they don't have great options. And so that's where we're focused with the study in patients that have those mutations with prior FGFR. And then we'll have some additional pipeline activities. I think we're excited to talk about them, and we'll save that for the future.

Awesome. That's exciting. Thank you, Todd, and it was a great concept. Looking forward to the data in the near future.

Yes. Sean, thank you very much.

Thank you.