Hi, everyone. My name is Maury Ray Crofton, one of the biotech analysts at Jefferies. I'd like to welcome the Tyra Management Team here. Today, we've got Todd Harris, the CEO, and Doug Warner, the CMO, joining us. Todd's going to start off, present some slides, and then we'll jump into a fireside chat format after that. Thanks for joining us today, Todd.
Yeah, thank you, Maury. It's a pleasure to be here. I'm going to make some forward-looking statements, so please be advised. Tyra is a company that's focused on precision small molecule medicine. We make our drugs in-house. We use the SNAP Chemistry Design Platform, which is a structure-based drug design approach, and that's led to our lead drug, which is an FGFR3 selective inhibitor, dabogratinib. Recent progress: we actually just got this drug cleared to proceed with a phase II study in upper tract urothelial carcinoma. We'll talk about that. We're in 2 other phase II's where we're dosing patients, one for intermediate risk NMIBC and the other for achondroplasia. Why FGFR3? It turns out FGFR3 is a genetic driver for a number of very important indications. Highlighted on the right hand of the slide here are urothelial indications.
What you'll see is that within bladder cancer, nearly half is FGFR3 positive. In the early stage, these are the non-muscle invasive bladder cancer, intermediate risk, or in the low-grade upper tract urothelial, FGFR3 positivity is extremely high. It's 70%, 80%, 90% FGFR3 positive. In the metastatic setting, it backs off a little bit. It's a selection bias down to being about 15%. We'll talk about that a little bit. J&J highlights with a pan-FGFR that they're moving forward in this space, that this is a $5 billion-plus market opportunity for them. That's because of the level of unmet need in patients, the very high volume of patients, especially in the intermediate risk NMIBC setting, and the high rate of FGFR3 positivity. In addition, FGFR3 is the driver for several very important skeletal dysplasias.
Achondroplasia, or the most common form of dwarfism, is caused by an FGFR3 alteration across germline. There are another 40,000-plus kids with FGFR3-driven short stature conditions. In all of these, because they are FGFR3-driven conditions, our lead drug, dabogratinib, which is an oral FGFR3 selective inhibitor, has the potential to make a very significant impact. When you look at the competitive companies pursuing agents in all of these spaces, we are the only FGFR3 selective oral drug that's moving forward. The biology, this is a receptor tyrosine kinase. Typically, it expects ligand for signaling. In bladder cancer, these mutations, these are cysteine mutations or a fusion, hijack the machinery. They stitch this dimer together and cause constitutive activation. As a result of this, FGFR inhibitors, including erdafitinib, have been studied in bladder cancer already.
Erdafitinib is approved in metastatic urothelial, has a 35.3% ORR at the 8-9 milligram dose. Recently, Johnson & Johnson published a paper where they used erdafitinib at a much lower dose in the intermediate risk NMIBC setting. What's phenomenal about that is the CR rate was actually 89%, highlighting that for these low-grade tumors, they are very responsive to FGFR3 inhibition. For us, highlighting that this is a very attractive place to go with a selective inhibitor. Beyond just the 89% CR rate, they also highlighted that at 12 months, for any patient that stayed on drug, the durability was 100%. It's a phenomenal outcome for a phase II study when you compare that across anyone else looking in this non-muscle invasive bladder cancer setting. The challenge with the drug has been the toxicity.
Because it also hits FGFR1, 2, and 4, you have an incredibly challenging profile, especially from the FGFR2 activity, including PPE syndrome, nail disorders, stomatitis. From FGFR1, you have hyperphosphatemia. In this study, they actually dose-reduced from 6 milligrams to 4 milligrams in 61% of patients. Despite moving that dose even lower, the target engagement was sufficient for a really great result. We read out data last year where we compared a dose of 90 milligrams, which was highly effective in the metastatic setting, generating a 50% ORR against erdafitinib's dose in the metastatic setting at 8 or 9 milligrams. Demonstrated on the FGFR2 and 1 associated tox, we nearly completely mitigated all of it by designing an FGFR3 selective drug. Nail disorders, which are typically 70%, we saw at 7% or 1 patient. Hyperphosph, which is typically 76%, we saw at 13% or 2 patients.
Significant reduction in the diarrhea. The one thing that was similar across these profiles was AST and ALT increases. These are asymptomatic, largely low grade. When you look at any TKI used at a high dose to cover an IC90, these are the type of LFT measurements you would see, whether it's a pan-FGFR inhibitor, MET, RET, EGFR, or ROS inhibitor. What was remarkable is when we actually looked at the 22 patients we treated at either 40 or 60 milligrams, which was less than the 90 milligram dose, that transaminitis, those AST and ALT increases actually completely went away. Back in our fall disclosure, we highlighted the one patient that had a grade 1 ALT increase. It turned out on query, this patient's actual highest measurement was on baseline before they went on drug.
We really have a clean profile at the 60 and 40 milligram doses that for us are extremely relevant for non-muscle invasive bladder cancer, as well as what we're doing in achondroplasia. This is the study that's open and enrolling. We dosed our first patient in the summer. We're testing 50 and 60 milligrams. This is target engagement that we predict is very similar to the erdafitinib 6 milligram dose, where I showed that really high rate of efficacy. This is also that safety profile, the dose that that safety profile, which was quite exceptional. We'll be looking at 3-month CR data as our initial readout. What we've guided to is that the first 20-30 patients' data of 3-month CR could be available towards the end of the first half of next year. One final comment on the non-muscle invasive bladder cancer setting.
As we've gone out and talked to urologists, there's a ton of enthusiasm about this for their patients as a non-invasive, non-intravesical approach. People often ask, don't urologists really like to get their procedure revenue, or isn't buy and bill a major driver for their practice? The answer is yes. The answer is also that over the last 15 years, due to the advent of the oral prostate cancer drugs, most community urologists have set up an in-office dispensed pharmacy so that they can share in the economics of an oral drug as well, just like they do with buy and bill. That's actually led to their practice revenue, oral drug dispensing being the biggest driver of returns.
With oral prostate cancer drugs coming up on loss of exclusivity and going generic, we're finding that a lot of these urologists are very excited about bladder and an oral and where they think the space is going to go, highlighting this is probably where prostate cancer was 15 years ago, with an oral drug being an amazing option and then being able to successfully prescribe this drug and participate in the economics just like they do with buy and bill today. One more important update we just made was expansion into upper tract urothelial. The way to think about this disease is it's much like the non-muscle invasive bladder cancer space. These are low-grade lesions, but it's where the lesions move up through the ureter and into the kidney. It becomes very hard to access and very hard to surgically remove.
As a result, this is a really high burden unmet need. Standard of care, if you can't ablate these tumors, is that you're going to lose your kidney. FGFR3 positivity for low grade is 85% plus. Approximately about 3,000 new patients are seeking treatment every year. You use these rigid scopes to try and access the kidney, either to remove or ablate a tumor. Despite all of that, most tumors are going to recur within 3 years. Larger tumors are going to recur 90% of the time, medium 4.9 months. Many tumors are missed. There is one approved therapy here, and it's Jelmyto. This is UroGen's drug. You can see the picture here of how this is administered. This is actually access point is inserted through the back into the kidney to try and essentially administer this chemo gel to address treatment.
It's a very burdensome set of steps on the patients. This is administered over six weeks. Despite that, it's a very modest CR rate. No one else is really pursuing a therapy now. When we started our NMIBC study, we were actually approached by doctors asking us to study this indication. There's an extreme amount of enthusiasm because of what an oral FGFR3 inhibitor could do to reduce this or minimize this unmet need. While it is a relatively rare population, this is a population that would likely want to stay on drug to spare their kidney year after year after year. We think of this as a little bit of a Gleevec type opportunity in the sense that patients can amass significant benefit over the years just by having the daily oral to inhibit FGFR3. This is the study design. We've got 2 doses.
It's very similar to our NMIBC study. We'll look out to six months to give patients a little bit of better chance to see tumors remove and avoid that potential loss of a kidney as a result of the progression of the disease. All right, just finally switching to achondroplasia, another really exciting part of the FGFR3 story. Here in the mutation, actually, it's not a constitutively active mutation. It's a mutation that occurs in the membrane, stabilizes FGFR3 so that you get overexpression. The primary role of FGFR3 in the body is to regulate bone growth. It's a negative regulator of bone growth. Very interestingly, kids who are having achondroplasia on average are going to grow 4 centimeters per year versus a typical pediatric population of 7.6 centimeters per year.
There is some really good data now showing what does FGFR3 inhibition do while the growth plates are open. The first was BridgeBio shared their infigratinib study, which used one-sixth of their full oncology dose and was able to get a modest 6-centimeter annualized height velocity improvement. Not quite to where you want to be, but nonetheless, a really exciting option for patients that's similar to what the CMPs got. What they didn't test was going to higher doses. When folks have tested higher doses, and this was a study done at Memorial Sloan Kettering Cancer Center on the right, for kids that have had pediatric glioblastomas that you would expect to be growing 7.6 centimeters per year, they grew 19 centimeters per year on a full target inhibition of FGFR3 with an oral inhibitor.
That's a very significant leap up, so much so that you actually have bone integrity challenges, and you saw SCFE and fractures as a result. There's a really good genetic basis for what we're doing. Not only do you have kids with achondroplasia with the overexpression of FGFR3, but you also have a syndrome called CATSHL, where one of your FGFR3 alleles is knocked out. This would essentially be half the FGFR3 expression. These males are going to grow on average 6 foot 5 instead of the typical 5 foot 9. Their bone integrity is actually quite strong. You can get some pectus excavatum and some waviness in the fingers just due to the rapid amount of growth. The bone integrity is actually strong. Preclinically, we can recapitulate this phenotype. If you have a double knockout of FGFR3, it's lethal.
If we provide a full oncology dose to a mammalian species here, we've got a mouse, but we can repeat this with rat and dog. What you see is the animal is going to grow so quickly, they're going to get fractures, and it's going to be a severely toxic dose. If you drop that down to about half the oncology dose, what we typically see is that the animal's bones are all growing longer and that they tolerate it very well. This is a great preclinical validation of sort of what we see genetically, that if we target moving FGFR3 expression down in about half, we can get the long bone growth, but not with that severe toxicity. I highlighted this example in the clinic where full oncology doses have led to very significant jumps in growth.
Kids are jumping off the growth charts, but it's coming with some toxicities. What are our expectations with this program? There are 3 competitors ahead of us. They're creating great options for patients. In phase II and III, all of these companies have generated what's essentially about a 6-centimeter AHV benefit. In the case of CNP, you can increase the dose in these kids that are 5 to 10, and the AHV benefit does not grow beyond 6 centimeters. It's capped by the FGFR3 brake that's on. In the case of infigratinib, BridgeBio very thoughtfully moved the dose up to this amount. It was an amount just before they expected to start seeing hyperphosphatemia. They were able to get to 6 centimeters. This was one sixth of the oncology dose.
What we talked about is that if you do move all the way the oncology dose, you're going to get to a 19-centimeter amount of growth, and that's going to come with some toxicity. Where's the right amount? We think BioMarin generated some really good data in short stature conditions that are not FGFR3 driven. There, they were able to use their dose response CMP to take kids from 3.7 centimeters to 8 and a half centimeters. It's a great benefit for these kids. These are idiopathic short stature kids or Noonan syndrome kids. This is what we want to accomplish with this program. We want to double the efficacy in the kids with achondroplasia that everyone else has been able to generate. You can't do it without an FGFR3 selective inhibitor. Importantly, it's not just about annualized height velocity.
This is the surrogate endpoint. If you do this, if you inhibit FGFR3 the appropriate way back to what would be a typical physiologic setting, the hope is to improve disproportionate short stature, improve reach, frame and magnum stenosis, reduce surgeries. That is what the community and we care obviously most about. We have 4 doses we are testing in our phase II study. When we get to the second, third, and fourth doses, we are getting to target engagement beyond where BridgeBio achieved with that one sixth of the oncology dose. We are getting right up to that half the oncology dose where we do not necessarily want to move further because we feel like it is within these doses that we can really optimize without pushing growth too far. This is the study design. We have a sentinel cohort that we are recruiting.
We're happy to announce that we've cleared the first dose, and we're on to the second dose. We'll be moving through the third and fourth dose pretty shortly here as it's just a 30-day window. We've seen huge community engagement such that we actually have a final of patients scheduled out as we move through each of these sentinel dose cohorts. We're also enrolling kids into cohorts 1 and 2. The key difference here is the sentinel is age 5 to 10. There's no run-in period to wait. They're getting treatment right away. We have highlighted that we're treating at least 3 kids. In fact, we have such a strong interest in the study, and we have opened this up to both treatment naive and treatment experienced that we're recruiting and putting slots forward for more than 3 children in each of these sentinels.
The data readout we're expecting in the second half of the year is all of these doses. There's going to be at least 3, but likely more kids in each of those doses, and we're going to look at the six-month AHV. All the while, we're recruiting kids that might be younger than age 5, like 3 and 4, as well as other kids that don't make it into the sentinel, into our cohorts 1 and 2, treatment experienced and treatment naive. Just a reminder, achondroplasia is the tip of the iceberg here. Hypochondroplasia is another FGFR3-driven condition. Shock mutations, laryngeal dyschondrosteosis, and Turner syndrome as well. We expect that with the appropriate amount of FGFR3 inhibition, you can have a best-in-class profile for all of these indications. When we get to idiopathic short stature, BioMarin's generated some good data.
They've gotten to 8.5 centimeters per year. It's going to be with an injectable. We too think that we can generate very compelling data here with an oral. You can only get here with an FGFR3 selective oral, which is key. This is an exciting, expanding market opportunity that we'll ultimately pursue with dabogratinib. Just to summarize some really exciting milestones, we're going to have data both in NMIBC and in achondroplasia next year in 2026. We're well financed into 2028 with $275 million in the bank. We're going to look for data readouts next year, obviously, to move dabogratinib forward in potentially multiple indications in phase III. Thank you. Maury, if you want to, Doug and I are here if you want to pepper us with questions. Sure. Yeah, I'll just do some questions.
I think the slides were really helpful, and congrats on the progress. Maybe just starting off for NMIBC, since that's going to be your first update for SNÅP next year, talk about how you're setting expectations for that. You showed the THOR-2 data there. I guess you want to be as good as that in efficacy, or could you be a little bit lower with better safety?
Yeah, you want to tackle that, Doug?
Yeah, when we talk to treating physicians and key opinion leaders, they say, given the advantages of an oral option, they potentially would be satisfied with a lower bar for efficacy, say 70% complete response rate. Certainly with the Thor 2 final data that was just published, it's really encouraging that we might not have to sacrifice any sort of efficacy by targeting the FGFR3 receptor and avoiding this toxicity as well.
Got it. You have got 2 doses with 50 and 60. What are the expectations there? Do you anticipate seeing something different with the 2 doses?
When we did the parallel analysis of the erdafitinib exposure at their reduced dose, their metastatic dose is 8-9 milligrams. Their dose in THOR-2 was 6. That's around likely an IC50. 60 milligrams qD from dabogratinib covers the IC50, so that should be sufficient. When you look at the THOR-2 data as well, you had 60% of patients dose-reducing to 4. We think we're going to analyze both doses to see the overall toxicity and efficacy to try to choose sort of the best dose, considering how sensitive urologists are to toxicity and managing chronic toxicity in this type of setting.
Got it. Okay. For the update, are you going to have all patients from both cohorts, or is it going to be a smaller number of patients in the data? I guess how much follow-up beyond the 3 months could you potentially have?
For the data results that are going to be available at the end of the first half of next year, we're hoping to have 20-30 patients overall combined in the 50-60 milligram cohorts. It's randomized, so we anticipate equal numbers of patients in each cohort.
Got it. Okay. I think the slide you showed about just the commercial opportunity and the buy and bill versus having an oral, I guess, how do you see the treatment landscape shaping with an oral option? Do you think your drug could be used as a first-line therapy in turbinate refractory patients, or how do you see that?
Yeah, you know I think that this is a market that we really expect to be a switch market. When you think about what's first line, second line, third line, I just don't think the urologists are thinking about their patients that way. What they're thinking about is, "I treated this patient, gave him TURBT last year. Now they're back. They have another one. What should I do? Should I give them more chemo?" I think it's amazing that all of this work is going on for multiple intravesical options and an oral option for these treating physicians. I anticipate it's going to be based off of their preference and experience with each of these. I think that the oral experience has the potential to really change the game for both the patient and the urologist.
The urologist spends a lot of time administering some of these procedures. If it could be done with a simple oral option, given what we talked about with practice economics, they shouldn't be disincentivized to do buy and bill or oral from the way they've set up their practices. I think this is going to be a great option that they're going to consider for many of their patients. If the patient doesn't get a response on dabogratinib or TARG-210, I think there's going to be switching to try other things because these patients aren't going to—they're not necessarily at risk of dying in 5 years. Progression is really low, but this is a disease of significant burden coming into the office again and again and again, going under general anesthesia for surgery, getting chemo installation.
I think all of these are going to be great options. I think you're going to have preferences by the physician and patient that'll cause a pretty dynamic switch market.
Got it. When you turn over the cards for this data update next year, and if you see what you need to see, is it going to be enough data to move to a registrational study? Maybe just talk about what the next steps could look like.
Yeah. TARG-210 had, I believe it was about 30 patients, about 15 in each, to make their dosing decision for phase III, and they moved right into the Moonrise one study. I think that's enough of us to get the signal we need to run what could be a similar randomized study as they ran, a similar study as CG Oncology ran. It could move us pretty quickly because they've really clarified, I think, a regulatory path that FDA is looking for companies like us to follow.
Got it. Maybe a couple of questions on achondroplasia. You've got through the first cohort. For the update, second half of next year, you're going to have patients from all the sentinel cohorts. You can't say exactly how many patients you have there. Can you say how much annual height velocity data you're going to have, how much follow-up? Maybe say.
Yeah, I mean, it's going to be the six-month data that we're expecting to have. What's nice is all of the other competitive products have reported out six-month data so that we can certainly benchmark. What we're telling folks is we're looking to improve upon the efficacy. We can really prove the concept. Are we enhancing AHV beyond what all these other agents were able to do even at six months?
Yeah. And with normal height, you've got 7 and a half centimeters. You want to go above that. I guess maybe just talk more about the rationale for wanting to go above.
Yeah. If you go to the patient advocacy conferences, you're going to hear physicians talk about adding bone lengthening surgery on top of vosoritide. Why are they doing that? They're doing that because they're looking for additional benefit that they're not going to be getting from these current agents. If there's any opportunity, most of the kids will have been on either not on a treatment or on a treatment that isn't quite hitting the mark. If there's any opportunity for additional catch-up growth in the last little bit while your growth plates are open, I think that's going to be welcomed. We certainly hear that from physicians and families.
Got it. Okay. There is another big event happening early next year with the BridgeBio phase III readout in achondroplasia. What potential read-through do you see from that study to your program, and what would be best and worst-case scenarios?
Yeah, rooting for their success, certainly for the benefit of patients. I think if you look at their phase II data, the expectation is they're probably going to hit about 6 centimeters per year. That's going to be incremental over 4, which is the average rate of growth. That's similar to vosoritide and Ascendis. I think people ask, well, what kind of FGFR1 or 2 toxicities? They've really chosen a very low dose, and I think that's a very thoughtful approach with their drug to try and minimize hyperphosphatemia and some of the FGFR2 toxins. Because they're getting target engagement on FGFR3 to improve height velocity, they may get some target engagement on FGFR1. You might see a little bit of that, but it's probably going to be low-grade and probably still an acceptable profile. That would be sort of my read from where we're sitting today.
For us, I think it's a great outcome if they can get to six. We're going to be rooting for them as they go get into the marketplace with that. I think it highlights that our approach to push target engagement further with the therapeutic window that we have is going to be really valid. It should set us up well for the second half of the year data readout.
Got it. Okay. Thanks so much for joining us today, Todd. Doug.
Yeah, thanks, Mark.
Thank you.