Tyra Biosciences, Inc. ($TYRA)

[Audio Gap] conference on [indiscernible] Las Vegas. I'm very pleased to be up here this morning with Todd Harris, Chief Executive Officer of Tyra Biosciences. Todd is going to run us through a few slides, and then we'll open up to Q&A. So Todd?

Thanks, Jason. It's great to be here. Thanks for having us. So I will be making some forward-looking statements today. Excited to highlight just upfront here, what we talk about when we talk about Tyra and our [indiscernible] strategy. It's a very exciting year for us. It's a very exciting few years coming up for us. We have 3 potential blockbuster indications going into late-stage development with our lead drug, [indiscernible], a drug that has been validated in a Phase I study in a late-line metastatic as being in a highly selective, very well tolerated FGFR3 selective inhibitor. It's touched over 100 patients today. And in the 3 indications that we're talking about, these are validated indications where FGFR3 inhibition has already demonstrated very meaningful outcomes, but where the current drugs by inhibiting other isoforms have run into significant toxicity challenges. It's where [ davegratinib ] can truly stand apart. And to just highlight these indications, and they're quite compelling. In urothelial carcinoma, there's about 80,000 new patients a year. There are 700,000 patients worldwide with bladder cancer. FGFR3 mutations, and they're very specific ones, drive nearly half of these. But in the intermediate risk setting, low grade and in the low-grade upper tract setting, 75%, 70%, 80%, 85% rates of FGFR3 positivity. So this is where the disease is really driving, or where the gene target is really driving the disease, and it's exactly the gene target that we hit. These are really large opportunities. I'm talking about it. In addition, FGFR3 is the driver alteration, the overexpression of FGFR3 that drives achondroplasia and several other skeletal conditions. Combined, these represent really meaningful opportunities to change the game for patients and to change patient care. We are, in many instances, the first in class and the potential best-in-class treatment option that could be delivered here. So let's actually start with what would be the biggest opportunity for us. It's the intermediate-risk [indiscernible] indication. And just to highlight the scale of this, we're talking about 35,000 new patients a year that are FGFR3 positive that could be addressed. This is actually really comparable size of the market but a very successful drug called [indiscernible] or [indiscernible] targets. There, EGFR-positive lung cancer, there's about 33,000 new patients here in the U.S. The average treatment duration of that drug is about 23 months. The average treatment duration we anticipate for [ davagratinib ] is also going to be about 2 years. That drug [indiscernible] is about a $7 billion drug and has truly changed the game for EGFR-positive lung cancer patients. That's the type of opportunity we're talking about here when we talk about the intermediate risk NMIBC. And let me just highlight a little bit more about why. And to do so, I really want to focus on the patient journey, and I'm going to ask the audience and those listening to go through an exercise with me. I want you to imagine 30, 40 years from now, you wake up on morning and you see blood in your urine. That's the first diagnosis of a potential bladder cancer. Now you're going to call up your primary care doctor, they're going to tell you to get to your urologist, you're going to look at the urologist and realize, okay, they're probably over 30 minutes away from my house, you're going to schedule an appointment and you're going to show up in the office. And when you show up in the office, the diagnosis will look like this. You're going to be asked to lay out on a table. You might have a young nurse put the cystoscope up through your [indiscernible] after a little bit of a numbing cream. And then while you're there live, the physician is going to look around and see the bladder cancer lesions and give you that diagnosis. Now you go home at that point, and it's pretty daunting. You look up you see that survival rates, if you're in the metastatic setting, can be very poor. You see that if you're muscle-invasive or even high risk, you may lose your bladder. And you see that in the intermediate risk setting, you are not necessarily going to lose your bladder, but the recurrence and the frequency of procedures can be quite intense. Obviously, you're hoping for the best case, the physician is going to go ahead and schedule you for a treatment to remove the [indiscernible]. You're going to come back 2 weeks later. You're going to lay out on the table fall asleep. But when you wake up, the physician will have used one of these devices to selectively cut out with a hot wire, each of your tumors collect them. And at that stage, we still don't know necessarily what grade you are. The physician is going to send that out for pathology. Tell you to go home, rest and give you a call maybe a week or 2 later. So in a great scenario, you're going to get the news from the physician, good news, your intermediate risk. That means you have a low risk of progression. The challenge with your disease is that you may need frequent repeat procedures if you continue to recur. It's at that setting that we hope to really change the game for the patient. Today, all your offered is a wait and see and a repeat surgical procedure. Or if you want to tolerate it, you could be invited to come back once a week for 6 weeks, once a month thereafter, to get catheterized by that young nurse and to have chemo pushed into your bladder and to be asked to sit there for hours on end, potentially trying to hold it in. And then do that week after week after week with potentially even modest results. But a huge burden on the patient for going in. And actually, the scarring and the end result on the bladder itself, this can lead to just fibrosis and a significant deterioration of bladder. Now in today's setting, there are new treatments coming. Now all of these treatments involve urethral violation. So the story just got approved. This would be a once-a-week push chemo gel instead of chemo into the bladder. CG Oncology is looking to advance [indiscernible] This would be a once-a-week pushing of viral vectors through a catheter into the bladder, potentially quarterly thereafter, maybe re-induction with once a week for 6 weeks as well. Or J&J, which is pursuing the [indiscernible] which involves inserting and removing every 3 months, a pretzel that stays with you every -- really minute of every day. And it's something you feel it's something that create urgency UTIs and other challenges. If we are successful, 1 day, a physician will be able to say, after your turbot diagnosis and low-grade diagnosis, I could drop ship you a drug. Just take a pill day, and we'll just monitor you over time, but this has the potential to reduce your occurrence. So hopefully, I've been able to articulate why what we're doing could mean so much for changing standard of care for patients. Now the reason we believe, and we benefit immensely from some of the leading work that J&J did with erdafitinib is that erdafitinib provided at a lower dose, showed a great CR rate in a study that looked at marked lesions in the intermediate setting, 89%. And for any patient that could stay on drug, the durability was 100%, which is remarkable. But mechanistically, actually it will make sense. Once the tumor has been reduced, as long as you stay on that drug, you put daily pressure to keep those lesions from growing dock. Now the challenge with this drug was the tolerability. And it was the tolerability due to the FGFR1 and 2 associated [indiscernible]. Things like hyperphosphatemia, eye disorders, nail disorders, mouth [indiscernible] that led to a reduction in 61% of patients. Despite that, even with dose reduction, you saw this good activity. [indiscernible] move to -- put this into the pretzel to get local delivery, that reduced the systemic talk, which is a great outcome. They got to an 81% 3-month CR, so they were able to get to similar levels of efficacy and they've advanced this now into their [indiscernible] study, their Phase III. But when we look at what it looks like to have some of these intravesical therapies, or even the pretzel place in the bladder, you can see that these are still associated with significant local AEs. Things like 48% frequency, or 44% UTI. Or they need to drink 1,500 milliliters of water or the issues with the urine becoming a biohazard after these events. So these are certainly not a walk in the park. We are in a current study, and we updated our guidance today to highlight that we're going to read out in August an initial data set here, where we're looking at 2 doses, 50 and 60 milligrams. These are the doses that we believe correspond in their AUC coverage to that efficacious dose, the erdafitinib used of 6 milligrams in the 402 study. We'll be reading out at least 10 patients of efficacy at each dose and quite a few more patients that have been on the drug for safety. We have enrolled well over 20 patients to date. We continue to enroll pretty robustly. So come August, we anticipate that we'll have at least 10 to 15 efficacy readouts, that's 3-month CR, as well as a detailed update on safety for likely well over 30 patients in this study. So a really important data readout that's coming. This is going to be the determination of a go, potential no go to Phase III. If we need to test another dose, we can so we can either move the dose up or down at that stage, if we feel like we're not quite getting there. And the market we've set for [indiscernible] is really hitting CR rate or better with the type of tolerability that we saw at these lower doses in our metastatic setting. Now the unmet need here is truly procedural burden and surgical burden. It's really only an oral option that can address that. The THOR 2 data sets the precedent with exceptional durability of 100%, and that daily pressure on the tumor. With our [ SERF302 ] study, we want to hit that 70% CR rate or better. We want to repeat the safety signal we saw in 22 patients treated at either 40 or 60 milligrams in our metastatic setting. To us, that's a -- would be a huge success and a go decision for Phase III. A lot of investors ask us, why is 70% enough. One important thing to keep in mind is this is a window of opportunity signal-seeking study. We intend to move into a Phase III in an adjuvant setting. Where we're not going to be looking at CRA [indiscernible] looking at disease-free survival. The expected disease-free survival at 2 years by doing nothing, which is often standard of care today is about 60%. You can have about 40% of patients recur. We anticipate with a compelling hazard ratio, getting to a 78% disease-free survival or better would be an exceptional outcome. And really the minimum bar here is all we would need to show is that [indiscernible] that have been able to stay on drug for 2 years that we've reduced the risk by 45%. That's a 45% 24-month CR rate. If we hit that 70% 3-month CR with excellent durability as we expect patients can tolerate the drug out to 2 years, we have a high degree of confidence we can have a very successful Phase III outcome in an adjuvant setting. One final point on the intermediate risk setting is just this A lot of folks ask us about what about the reimbursement? Buy-in bill is a strong incentive to use these procedures in this setting. Well, the reality is in the community urology setting where 70% to 80% of patients with intermediate [indiscernible] treated, many of these community urologists now have their own in-office dispense pharmacies where they've contracted with our GPO so they can have a spread on oral drugs, just like they do for buy and bill. That's led to a giant increase in their practice revenue coming from oral drugs, especially drugs like [ XTANDI ]. And some patients are seeing upwards of 50% or more of the revenue coming from these oral drugs today. So there's a strong incentive for the physician. It's a strong incentive for that patient. It's really great alignment. And really no one's brought an oral treatment through bladder cancer in this setting before. We've got the oral prostate cancer drugs being used in [indiscernible] very successfully. This will be, I think, a game-changing and revolutionary first. So just a couple of other points before we get to Q&A. We had our first patient dosed in UTUC that we announced today. This is very exciting. So it's actually a study that we anticipate moving to our first approval. That's because the registrational path is a bit more straightforward. [indiscernible] is able to get to full approval with a 70-patient single-arm study. A little bit about this disease. It's a rare disease, about 3,000 patients, 85% are FGFR3 positive. What we're talking about is the same lesion in the bladder that drives nonmuscle invasive bladder cancer, intermediate risk, but the low-grade lesions showing up in these ureters and the renal pelvis where it's very hard to access with surgical devices. Most tumors are missed leading to [indiscernible] patients, nearly half getting [indiscernible] or their kidney removed. Where treatments are used. It's in an effort to save the kidney or to spare the kidney, but you still see high rates of recurrence because of how hard it is to actually access and remove these lesions. We want to prove therapy as the chemo in the [indiscernible]. This had a CR rate of about 58%, a duration of response of 56%. So about 1 in 3 patients are actually benefiting. You can see here, this isn't without a lot of challenges this bag, and hole that's essentially drilled through the back to try and get the chemo the renal pelvis is not comfortable or easy to deal with. It's only addressing a small number of tumor sizes. When people ask us, why is this a blockbuster opportunity? A drug like [indiscernible] only do maybe $100 million, $125 million in sales. There's really a few key drivers. One is [indiscernible] price like chemo and a gel. There's certainly premium pricing here that we're seeing in the high-risk setting that's very acceptable to spare an organ. So I think you can look at a 4 to 5x increase in potential sales with a premium and innovative product. Additionally, only about half of patients can really be addressed with the with [ Jelmyto ] because if your tumor is bigger than 15 millimeters, or if you're in the [indiscernible]. So now you're talking about an opportunity that's potentially 10x, what we would see [indiscernible] The last thing is really the ability to change the patient experience, not just in the first year, but for years on end. This could become a prevalent population of pace that have truly spared their kidneys and all the comorbidities associated with that, that would stay on drug, not for just a year, but potentially multiple years as an oral drug staves off recurrence. So we're in this study, [ SERV-303 ]. We're guiding to initial data next year. We're testing two doses, one dose overlaps with the IR NMIBC setting, one dose is a little bit more. Finally, in achondroplasia, just highlight that we had an exciting announcement today. We are cleared on our fourth dose. That means we have kids, at least 3 or more that are dosed at each of the doses, the 4 doses we're testing in our safety sentinel cohort. That means that the patients that -- or the kids that have been going into Cohorts 1 and 2 are not eligible to be receiving any of these doses when they come up for treatment after their 6-month run in. And we'll be reading out a 6-month efficacy dose response analysis from the safety sentinel in Q4 of next year. We shared something really quite interesting and exciting. This is an early scientific experiment, but it showcases what FGFR3 selectivity could do. This was data that one of our scientists shared this past week. A prenatal dosing in a [indiscernible] model. [ SynCon ] doses, when -- these are the especially the growth plates of the [indiscernible] magnum are often fused at birth. We see this preclinically in the [indiscernible] models. What that means is that, that [indiscernible] magnum stenosis that can lead to significant surgeries in these kids that contributes to the 50-fold 100-fold increase in [indiscernible] death syndrome is really driven by something that happens late in the third trimester. So we actually treated pups and their [indiscernible] with [ davagratinib ] in the third [indiscernible] And where wild-type expectation for SynCon Jersey's fusion is zero, when you look at this model of [indiscernible] that they kind of play settings these fusions are up in the 3s or 4s. With treatment with [indiscernible] right after birth, see a nice reduction. But if you combine that with prenatal testing, and after [indiscernible] treatment. You see that on the far right, you can see we've almost entirely normalized of reducing or removing the fusion of [indiscernible] in this animal model. So a really exciting compelling results that can be achieved with an FGFR3 selective drug. So that's that. It's a great setup for data and opportunities. And Jason, happy to answer questions.

And boy, do we have them. Thanks for the great presentation, Todd. Maybe to start, you've outlined what you're looking for in the readout and NMIBC. Can you help us frame what sort of safety profile is ideal, and particularly given sort of this is an elderly population, they tend to be a little bit more frail because they've been smokers?

Yes. We like to point to the data set of 22 patients that were treated at either 40 or 60 milligrams. These are metastatic patients from our SERF301 study. That -- there was a rate of low-grade diarrhea about 18%. We had noted one ALT event. That was a 5% that was increased. Really nothing else of significant concern there, very low grade 3 events. So that's the type of profile that if we can replicate here now in the intermediate or NMIBC setting would be just a huge success. Now investors ask us, well, that seems like what about the diarrhea [indiscernible] not problematic? One thing we point to is you can look at -- there are several studies that XTANDI has done versus placebo. This would be a similar elderly patient population. And obviously, it's males, females. But placebo rates of low-grade diarrhea are upwards to 20% in some studies. So getting to something around 20% is a huge, huge success. That would be, again, repeating what we've already seen in the [indiscernible] setting. Low rates of ALT AST is important. If you look at [indiscernible] these are local treatments. The AST LT increases were 15% to 16%. So obviously, we would want to have very low rates, certainly look no worse than that. And we anticipate from the data we've already generated, we should be able to do that.

Got it. [indiscernible], again, [indiscernible] looking at that data, or 60%, I believe, dose interruptions, 80% dose reductions. What do you need to come in compared to those rates?

Yes, we didn't have any dose reductions or discontinuations at our 40, 60-milligram dose. Now that's not to say that in a large study, we wouldn't expect any in the [indiscernible] study, the [ TAR210 ] Phase II update, the discontinuation rate was about 10%. So we would be looking for low rates of discontinuations or dose reductions.

Maybe one more on patient preference. You can see a lot of puts and takes. Certainly, I think an oral option for males would be maybe a lot more preferable just given the physiology. But by the same token, some of our docs are talking about, well, if a patient is older, maybe we just do the turbot because there quality of life, or their length of life left just isn't long enough. What's the sweet spot for you? And realistically, I mean how much of the market share do you think an option like [indiscernible] can capture if it delivers as it performs as you expect?

A key point we'd like to highlight is we intend to run an adjuvant study. An adjuvant study means yes, you're going to stage a grade the patient with TURBT upfront. And make an assessment as to the benefit of then adding on a therapy, right? If you're adding on an intravesical therapy [indiscernible] chemo, it's not done a lot today because it's so bothersome. That same analysis may occur for a pretzel, or for intravesical viral vectors. If you're adding on an oral option at that point with benefit of reducing the likelihood of coming back for a TURBT, you could see how this option would be very favorable, not just for patients, but even for the physicians and their workflow and their practice as well.

Makes sense. Remind us again about how many patients are diagnosed at least in the adjuvant setting? And again, if the option becomes available, you think some physicians might hold a patient if they're kind of on the edge there at the border?

Yes, there's 80,000 new patients diagnosed with bladder cancer. So the majority of those are going to be in the NMIBC setting [indiscernible] low-risk intermediate risk highest you do the TURBT you're not necessarily going to know precisely what you got. So that's obviously a large amount of new patients every year. But in addition to that 750,000 patients living with cancer and many of those are going to follow on those. Those are [indiscernible] groups. So when we look at just the annual addressable population, we think it's conservative to say that 35,000 new patients seeking treatment every year with FGFR3-positive low-grade intermediate risk disease.

Makes sense. Let's pivot to UTUC. Maybe taking a step back, you've outlined, I think, a pretty compelling opportunity, but this was a shift from metastatic UC. Why is this sort of a better sweet spot for [indiscernible] relative to maybe the broader population in [ MUC ]?

There's a really interesting phenomenon that occurs when you look at this population, which is a selection bias away from FGFR3 being the driver as you get into more invasive disease. And you can almost interpret that. So in the metastatic setting, it's 15% to 20% of FGFR3 positive, in the low-grade immediate risk set, it's 80% plus. So what's going on? Well, there aren't 30,000 new FGFR3-positive metastat patients showing up. They're showing up with low-grade lesions. To me, that says FGFR3 is a sufficient alteration to start to drive low-grade lesion outgrowth. And then you typically look in the metastatic study, there's a lot of co-mutation. So there's other things you're adding on to start to break that low grade out into maybe something that's high grade or muscle invasive and metastatic. That all points to the best place to start with an FGFR3 selective inhibitor is in the patient population where FGFR3 is the primary driver and not intermediate risk setting. But the only way to play there is to have a very selective drug with exceptional tolerability. Because otherwise, these patients want to live their lives. They are burdened by the treatment paradigm of urethral violations and repeat office visits. You want that oral to be extremely well tolerated so it can just fit into their daily routine. Then you really changed the game for that patient.

[indiscernible], 58% CR rate I mean, ideally, what do you think Dave can deliver here?

So we've tested in market research and what we were really surprised by in the UTUC setting where you've got risk of losing your kidney, is that any meaningful CR, whether it's 30%, 50%, 70%, physicians will use the oral option first before anything else. The way they look at it is if I can address this with an oral option, I can avoid all the surgery, removing the kidney, all the other procedures, why not start there if it's not working for the patient, we've got other options. So what will drive, obviously, increased market opportunity would be the more patients getting to CRs and the more they then stay on it for a long period of time, that obviously grows the market. So we'd love to see that be an excellent CR rate. But anything 30% or higher, our market research suggests we'll get massive uptake because of this being such a preferred option to what they're facing today.

Is it fair to say that maybe efficacy should be around what we see from the upcoming NMIBC, sort of?

We're starting to hear this dialogue from investors, and I think it's a wise one that's a really meaningful derisking event for UTUC. Because there isn't reason to suggest it should be too different. There's experience with [indiscernible] in the in the intermediary NMIBC setting that was 89% CR, that's exceptional. There's experience with infragratinib in the UTUC space by [indiscernible] Now it wasn't as clear cut. They weren't all low-grade lesions, but 3 out of 5 patients in that study [indiscernible], they save their kidneys. And the response rates, even though they weren't all CRs, were upwards of 60%, 70%. So yes, I think you can expect this is an equally or similarly responsive lesion. So data in the NMIBC setting could be a really important derisking event for [indiscernible]

Got it. SURF 303, I know a little bit of ways away but help us frame sort of what benchmarks you're looking for and what kind of output would make you feel comfortable about moving forward in UTUC?

Yes. As I mentioned, that the CR rate can be lower here, 30% or better. We are testing a higher dose because efficacy could matter more and the willingness to tolerate some safety effects is higher given that the alternative [indiscernible] you lose your kidney or you end up with a hole in your back and a bag to put the chemo gel, or some pretty invasive surgeries.

Got it. Time we have left, let's go to achondroplasia. If you talk to most prescribers, AHV seems to be much more secondary. I mean, yes, there's quality of life issues. But for them, it's really the medical sequela associated with that [ sagittal ] spine and the [indiscernible] and whatnot. So based on the [indiscernible] data, how much do you think Dabo could improve upon those metrics? And what does that look like to the competitive field now, understanding we're still waiting for some data?

Yes. So I think the miring data gives us really exceptional hope that if you tune that FGFR3 activity back towards something that's more typical that you can really very early on, start to normalize many of the growth parameters across craniofacial [indiscernible] and [indiscernible], spinal stenosis and obviously, the long bones, which will drive your AHV surrogate endpoint. [ BioMarin ] just shared some really exciting data, and it looks like they're going to go to the FDA to get full approval, which is great. And that data shows that over time, that age fee benefit that seems to be maintained for multiple years starts to lead to meaningful changes in proportionality, tibial Boeing. So what's exciting for us is if we can start to hit an AHV difference from placebo that's more typical of actually changing this to someone with [indiscernible]. And that, for us, the target is you want to hit about a 2.7 centimeter per year, not the 1.5 to 1.7. So it's almost a doubling of the [indiscernible] That should directly lead to faster time to hitting these endpoints. Could even give us an opportunity to see in a 12-month randomized period. Actually hitting endpoints that others haven't. So we're really encouraged by that data. We're obviously looking at what are those endpoints that we might now look at in a 12-month randomized setting if we're really hitting the HV mark that we lose to nearly double it.

Got it. Maybe a little bit premature, but let's throw this out there. Do you think that level of growth could drive maybe premium pricing?

Yes. I think a little premature. Obviously, we've seen what TransCon has done with their pricing. We'll see what [ BridgeBio ] does. I mean, look, this is we're looking to really provide the best-in-class solution. And there's already, I think, a great market here. Our market research, yes, suggests you could offers like premium by obviously beating these benchmarks, that's something that could go into consideration. But really, the focus is on -- for us, it is important with this program that we demonstrate best-in-class activity. We'll be the fourth market. So that that's necessary to be successful here.

Well, with that in mind, last question, help us frame the output end of the year. What are we looking for to make confident you're best-in-class?

It really comes down to at the highest dose or the highest 2 doses beating the benchmark set by others at 6 months. Those [indiscernible] were in the low 6s for BioMarin, for Ascendis in the high 6s for BridgeBio. So we're looking for a dose response curve that clearly points us into the sense potentially 8 at that 6-month period.

Perfect. Todd, thanks so much for joining us.

Thanks, Jason.

Appreciate it.