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

Perfect. Thank you so much. My name is Peter Lawson. I'm one of the biotech analysts at Barclays and I cover SMID cap oncology names and really pleased to have on stage with us the CEO, Todd Harris from Tyra Biosciences. And thanks for joining us.

To kind of lead the Q&A, and questions I've been asking on all these fireside chats is just like these kind of macro things around if there's any supply chain disruptions that you're kind of envisaging and how you prepared for it, whether it was COVID that kind of helped out, and -- yes, that's the first question.

Thanks, Peter, and thanks for having us. Yes. We -- I think it's a really good point. We thought pretty early about supply chain because of COVID. We actually thought very seriously before we did any of our work in China and other areas at that time. For the most part, on our supply chain, most of the -- our drugs are actually made in the U.S. in terms of raw materials, we might get from a few other areas, but this is a very small amount ultimately of our cost of goods. Any tariff impact really would be quite minimal [indiscernible] supply chain.

Okay. And then on the FDA cuts or potential cuts kind of anywhere, have you seen any slowdown in the communication or change in pace?

Yes, we haven't. Not in our direct interactions with them.

Perfect. And then I guess final question just around NIH cuts. I mean it's always disturbing longer term, but do you think you're reliant upon? Or is there any kind of secondary effect that we're not thinking about that whether it's clinical trial sites that -- dependent upon NIH funding?

Yes. For our business, no. I think for the broader community, it is -- it can be pretty impactful. So of course, all of us are hoping that America maintains its investment in innovation for, I think, the benefit of all of us.

Yes. Exactly. So just on to TYRA-300, which is kind of in the kind of oral FGFR3 side of things. So I wonder if you kind of set the scene of just like where we are and kind of what you're expecting to see over the next 6 to 12 months?

Yes. So our lead drug, TYRA-300 is we're pursuing some really important and large unmet needs in both oncology, where we estimate there's about 60,000 addressable patients a year in the U.S. alone with FGFR3-positive or FGFR3-driven bladder cancer. And in skeletal dysplasias where we estimate FGFR3 is a direct driver in nearly 40,000 children with open growth plates that could be addressed with an FGFR3 inhibitor. Those are just U.S. numbers alone. So these are really, really big and exciting opportunities. FGFR3 is a very important -- has a very important biological role in these conditions. And TYRA-300 was designed from the very beginning as an exceptionally selective FGFR3 inhibitor, sparing the other family members of FGFR that typically drive significant tox. And now we've seen that result play out in the clinic with the data that we released in the fall at the triple meeting. This is a very active, highly efficacious agent in late-line bladder cancer and really well tolerated, eliminating or reducing the side effects from FGFR1 and 2 and 4 that you typically see. With all of that, we're now positioned this year in launching our next Phase IIs. And it's an expansion into earlier-stage disease with intermediate risk NMIBC and an expansion that we've been planning for some time now to begin treating children with achondroplasia. So what you're going to see from us this year is significant investment and then operational execution of well-designed Phase IIs with very clear proof-of-concept readouts in terms of the safety and efficacy of the drug in these unique populations. So that's where we're at and that's the setup. We do have 2 other drugs in our pipeline, TYRA-200, TYRA-430. TYRA-200 is in the clinic and is advancing well. TYRA-430 is about to enter the clinic shortly.

Perfect. And then just on metastatic UC, kind of how does that profile compare to J&J's drug?

Yes. J&J has an approved agent, second and third line metastatic urothelial with FGFR3 positive, that's essentially a fusion or a point mutation that's well defined. In that population, they have a 35% confirmed ORR in their Phase III study and the durability of or a PFS of about 5.4 months. The key issue with that drug has been tolerability though. One in 70% -- nearly 70% of patients are actually dose reducing while they're on that drug, interrupting and a lot of discontinuations. And it becomes a very hard to tolerate drug while you're on it. Our profile, we saw in -- as soon as we got to 90-mg dose, we had 6 out of 11 or 54.5% confirmed ORR rate, which is really an exceptional number when you look at any of the studies that have been run in this space with monotherapy, that's really -- hitting above 50% is something that other agents don't typically see. EV doesn't see that. That's now first line, erdafitinib didn't see that. We even recently saw another competitive drug that has tried to move forward in the space with an FGFR3-selective, LOXO-435, there. Their confirmed ORR was about 41% once they got to the right dose, very much on par with erdafitinib. So we're seeing the [ trend ] of really exceptional efficacy. But that's balanced with something that we don't see, which is that very significant FGFR2 and FGFR1-driven tox with erdafitinib. So the 70% nail disorder, nail disease that you typically see on erda, we had 1 out of 15 patients with a low-grade nail disorder there. Hyperphosphatemia, you typically see that in 80% of patients. We're seeing it in the low teens. So these are really meaningful reductions in the very important AEs by sparing those other isoforms coupled with exceptional efficacy. So we're thrilled about how that's stacking up against erdafitinib, the data we just saw from LOXO-435. And importantly, it gives us really the opportunity now to move into the bigger, more exciting and higher unmet need populations in skeletal dysplasia and early-stage bladder cancer.

Perfect. And then kind of where are you in dose escalation for the 300?

Yes. So in the metastatic setting, we saw great efficacy at 90 milligrams, and we are testing a couple of doses above there to fulfill Project Optimus. We see with the efficacy, potential improvement in durability, yes, we see an opportunity to really just maximize the efficacy here by looking at a couple of other doses above 90 milligrams given how well it was tolerated. That will help us select the dose for the metastatic setting. At the same time, we're selecting a dose across the other key indications in our -- this year with our Phase IIs in achondroplasia and NMIBC. So we've got different doses positioned for each of these different indications with a very strong scientific rationale.

Got you. So you have 90, you got 100, I think, new dose and you've got 120. And so that's all part of the Project Optimus.

Yes. In our initial dose escalation, we went up to 120. We didn't see any DLTs at 120, so we didn't hit a maximum tolerated dose. But now that we have PK, PD efficacy data, we're really able to narrow down a dose that we think is going to be optimized for the best response and safety. And we anticipate that being somewhere between 90, 100 or 110.

Got you. Okay. When is the next update for that data set?

Yes. We haven't guided to it. We are not going to be dribbling out data. We want a fulsome data set at those doses for safety, efficacy comparison. So I think you could anticipate in a similar time frame that we'll be reading out some of our other data points in achondroplasia and NMIBC when we provide an update there.

Got you. Okay. And then what -- at that point, we'd have like a recommended Phase II dose, do you think?

Yes. We would either have 2 doses we're going to continue to test as part of Project Optimus in Phase II or if the data are clear and we align with the FDA, it can just be the dose we're moving forward with.

Got you. And then what's the bar for success there in terms of durability?

Yes. I think we want to improve upon what's been seen with erda. As I mentioned, that PFS of 5.4 months, we, for a long time, felt that, that could be achieved with a more tolerable drug alone just because of the level of dose reductions and interruptions seen with erdafitinib, we think that durability will improve with the drug that's well tolerated. Obviously, with more patients getting to deeper responses upfront, higher rate of confirmed ORR, that could also, we believe, extend PFS ultimately here. So yes, we'd like to see that durability improve. And then having a well-tolerated monotherapy option for patients in metastatic urothelial would be really one of the only drugs that would have that type of profile. I mean most of the drugs we're talking about here are chemo or an ADC, which feels a lot like chemo with EV, patients struggle to tolerate that. So -- and then you have erda, which also, if you talk to patients and investigators, feels a little bit like chemo as well. So this would be the one agent that patients could stay on for a very long time and tolerate well.

Got you. And then when would you open the Phase II? Do you kind of -- I guess, we get to see recommended Phase II dose or you'd start rolling?

This is, SURF301, the study here is a Phase I/II. So this is really when the data support that switch into Phase II, we'll make that, and it's really around having sufficient PK at the key doses we think justify a Project Optimus decision. So we're not really -- we continue to enroll robustly there. So it's not a major concern of when we switch. And I think we may learn enough right now to have a reasonable discussion with FDA around Project Optimus as well.

And then non-muscle invasive bladder cancer. What -- this data is late '25, I think, early 2026?

Yes. I haven't guided specifically, but I think you're thinking about that the right way. This is a condition -- that first endpoint is essentially a look at 3 months in terms of a marked lesion and its responsiveness. So CR, a confirmed response at 3 months is the metric that most have used now who are developing in this space. Anywhere above about a 70% CR rate, I think is highly attractive. That's the feedback we get from KOLs. It's on par with some of the other agents that are being studied like CG Oncology, UroGen and J&J's TAR-210. So that's -- that can come relatively quickly. And because it's a marked lesion that is addressed here with a systemic oral therapy, eradication of that lesion likely suggests that if you stay on drug, you'll have a very durable response.

And this is a lower dose and just the rationale for the lower dose? And what do you think the side effect profile would look like?

Yes. J&J did great work to, I think, highlight the opportunity here. They used a lower dose than their metastatic dose with erdafitinib. Erdafitinib is dosed at 8 or 9 milligrams. They moved down to 6 milligrams for this indication to try and improve the tolerability and saw a really nice response, an 83% CR rate. But even that lower 6-milligram dose still had the hyperphosphatemia, the FGFR2 tox that was problematic. So we're taking a similar approach. We too, in our preclinical studies, have evidence to suggest there's significant accumulation in the bladder over plasma. So many TKIs tend to do that. That obviously enriches the drug for the target lesion. And I think we're optimistic we've chosen a dose that's likely going to be quite responsive and also a dose that from our -- from the over 10 patients, we actually had 21 patients treated at either 40 to 60 milligrams. That was an exceptionally tolerable profile. So repeating that here plus seeing the efficacy would be, I think that's the TPP we're going for, that would be a major win.

Got you. And it seems like there's some interesting practice dynamics where you could leverage within the marketplace. Just talk about that component of the drug.

Yes. The urologists have seen a lot of patients, community urologists carry the majority of the load here on early-stage bladder cancer, non-muscle invasive bladder cancer. Today, these are treated with surgical procedures. So it's general anesthesia. And yes, that's reimbursed through procedural codes. In the future, though, with either a buy-and-bill or an oral therapy, you can really look to what they've done in prostate cancer now to see that all these various opportunities, replacing surgery with either an oral or a buy-and-bill procedure, are quite interesting and attractive for them. And they're certainly happy to move in that direction, and they're good for patients. What's quite interesting is the oral therapy has been the major growth driver for a urologist office. And that's a function of the AR inhibitors making significant headway with urologists prescribing them, and a group called UroGPO, that's contracted with pharma and then helps set up in-office dispensed drugs in all these community practices. That allows the physicians to see a spread on the pricing of drugs when they actually prescribe them. And so that helps incentivize them to manage any AEs and obviously track that patient over time. And it's become a really interesting way for them to expand their business, treat more patients and deliver to patients what most of them would prefer, which would be an oral drug as opposed to general anesthesia, surgery, multiple procedures, multiple visits to the doctor's office. So I think it's good for everyone, and that business model has been built up. It's been the main growth driver for urologists. And I think with bladder cancer, no one's approached this yet with an oral therapy, even though this commercial infrastructure is very much in place. So I think it's a really exciting opportunity. We're the only ones pursuing an oral here in the urologist office for bladder cancer. And we just added a member to our Board, Adele Gulfo, who helped establish a commercial product called ORGOVYX that leverage the in-office dispensed drugs in this way as well. That drug has been doing very good. It's a Sumitomo-Pfizer partner drug. And I think that's the type of model we're going to be looking to take advantage of with the launch of an oral bladder cancer.

Got you. And then achondroplasia, a really exciting space. What -- you're dosing the first patient this quarter?

Yes. The guidance is this quarter on dosing the first patient. We've been getting up and running here on that study. I think it's a really, really exciting moment in time. This is a drug that was designed very specifically for the alteration that is the driver of achondroplasia, FGFR3. So when we talk about this, certainly with the community, this is about targeting the condition at its source and maximizing the opportunity to improve the clinical sequela that isn't talked a lot about with achondroplasia. And that really is significant limitations in function and reach that have a day-to-day impact, but also significant comorbidities associated with pain, back surgeries that happen quite frequently as you get older. Those are the kinds of things we're hoping to impact early on here, and ultimately moving to earlier or younger children gives an opportunity to also impact things like sleep apnea and foramen magnum stenosis. So that's the goal. It's a pretty exciting point in time now for us where we've done a ton of work. We have a high degree of confidence about the molecule. I think we have a high degree of confidence around the doses that we've been able to choose here, being able to really optimize for the type of FGFR3 inhibition we want to achieve.

And then what dose levels are you testing initially? And kind of how does that kind of triangulate with, say, BridgeBio?

Yes. I think that the data is all out there for folks to see. If we just start from the experience with BridgeBio, which again, applaud the excellent work that they've done here in this space. They're now in a Phase III with the dose that they've selected. And certainly rooting for continued success for all these companies to have options for patients. I think what's interesting with the dose selection with BridgeBio, it's a pretty low dose. So in terms of FGFR3 engagement, you could predict from their -- the Phase I PK data that they've shared and published that you're engaging the target. You're not at an IC90, you're not in an IC50. You probably -- your continuous engagement is closer to IC10 up to IC20 from what the data suggests. And I think particularly in FGFR3, it does have a nice response, but they're just at the beginning of the dose response curve at that point. And you would love to engage FGFR3 more than that. That limitation there is when they're engaging FGFR3 with an IC20, they're engaging FGFR1 with an IC20 and pretty quickly start to see phosphate levels rise. And so that creates a barrier for moving up with that drug's exploration. We don't have that limitation. And it's really clear from the data that we just shared. We're not engaging FGFR1 meaningfully at doses up through our 40-milligram adult dose and beyond. And so we're able to hit FGFR3 all the way up to an IC50 average engagement, which we think is kind of the upper limit of what we want to test without seeing significant engagement from the other isoforms. Those are a set of doses that just haven't been explored yet. And I think we're looking to hopefully more quickly and more effectively have an impact on all those clinical sequela. The key surrogate endpoint that will point the way is annualized height velocity. And that surrogate has been pretty consistent with the low dose infigratinib and then Ascendis and BridgeBio. All those agents are getting up -- kids up to about 6 centimeters per year while they're on therapy. That's still underperforming the 7 to 8 centimeters per year that is physiologic growth. And in other conditions, agents like vosoritide, when it's not an FGFR3 driver, able to bring kids up to 8.5 centimeters per year AHV, and it's generated a ton of excitement about what that can ultimately do. We would love to see that and to really optimize the dose to move to that level of efficacy. That would more than double with what infigratinib is seeing and others are seeing, get us to a place where I think we could have a very safe outcome and then really look to optimize and improve upon the clinical sequela that's been hard for these other agents to really show a benefit yet.

Okay. Perfect. And then the first update, would that be towards the end of the year, into next year? Or -- and then how much data would we expect to see?

Yes. I think, again, not -- haven't guided specifically to it, but you're not off in the thinking. And as we talked about, a lot of our data points are going to kind of come in the similar time frame. Maybe with one exception that a really important endpoint here is going to be just the safety in our sentinel cohort at these lower doses. That data we're going to be enrolling out pretty quickly. We're going to be looking at 30-day DLT periods and then clearing doses. So that's data that does give us an opportunity to share this year. We're expecting to move through that. Then we'll be able to guide -- as we get through the first 12 children, we'll be able to guide to when an initial 6-month AHV would be and 12-month AHV would be from there. So you can expect some communication from us throughout the year on that.

Got you. And so that -- just to put a finer point on it for me. That the efficacy you want to show that's going to be the annualized height velocity and kind of what's your -- the go, no-go kind of thing for you?

Yes. So that's going to be -- yes, that's the key annualized height velocity with the safety sentinel cohort. What we're looking for is great tolerability, of course. And then we're going to have 12 kids. All of these should be active doses. And at least for the higher doses, the 2 to 3 higher doses, we would want to see annualized height velocities at 6 months that are well above the 7 centimeters that others have reported out at 6 months. And a meaningful dose response curve as we look at -- as we move up those doses pointing to what we think we're going to get to. At the same time, we're going to be backfilling cohort 1 and 2, which have naive and experienced children that will, I think, further enhance the robustness of those numbers and help us ultimately choose that Phase III dose. But I think that early look is going to be quite constructive.

Okay. Would you say you'd wait for those kind of higher doses, you wouldn't put these lower doses...

Yes. With the safety sentinel cohort, we're going to wait for those higher doses. That's also going to help us prioritize the doses that we continue to fill out in cohort 1 and 2.

Okay. Do you think that the industry, whether it's BridgeBio could change that bar of 7.5 over the longer term?

Yes, in terms of how their data read outs in Phase III?

Exactly.

I think -- yes, I think it's -- we're, again, rooting for the success of BridgeBio, of that drug for the benefit of patients. I think our expectations are that they'll probably come in around what they saw in their Phase II, which was a 6-centimeter per year growth. I think when we talk to the community, I think there's a clear interest in seeing more on the path to ultimately impacting the other clinical sequela more significantly.

Perfect. Okay. At the end of our time, but thank you so much. Really appreciate it. Great talking to you.