All right. Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference. For our next session, very pleased to have a fireside chat with Tyra, and it's my pleasure to introduce Todd Harris, the CEO. Todd, it's a privilege to have you here. Maybe I'll go ahead and hand it over to you to give a high-level overview of Tyra as it stands today and the various programs.
Thank you, Tyler. It's a pleasure to be here. We're really excited this week, just coming out of our earnings release talking about our Dabo 3x3 strategy. What is that? We have an amazing opportunity with our lead drug, Dabogratinib, in 3 potential blockbuster indications moving into phase 3 or pivotal studies, on data that we'll be sharing this year. Upper Tract Urothelial Carcinoma, which is a really high unmet need condition, that involves the kidneys and ureters with low-grade lesions that are just nearly impossible to remove surgically or even with Jelmyto, and often lead to individuals losing their kidney as a result. We're gonna be studying 2 doses of Dabogratinib orally in this indication. The registrational path here, as set by Jelmyto is relatively rapid.
This is quickly, while it's the newest study, we're opening up one of the, potentially, fastest paths to market, and it's a blockbuster opportunity when you look at the unmet need and the premium you put around essentially saving a kidney for these patients. In NMIBC, it's intermediate risk. FGFR3 drives the majority of these low-grade lesions, just like the upper tract. It's our standalone largest indication that we're pursuing. We'll be having phase 2 data that'll come out, that we're guiding to mid-year. That should be enabling for us designing and kicking off a phase 3 study. This is an incredible opportunity as an oral drug that hits the driver of the disease, FGFR3.
We are the only company and the only individuals pursuing an oral option here versus the burden of intravesical and surgical treatments that are managing these patients today, but not in a way that's very easy. Third, achondroplasia. This is again a disease driven by FGFR3. Great data from BridgeBio that we saw. Really excited for that. We think this is gonna be a great oral option that's delivering on the type of height benefit that the CNPs have seen. What we're hearing from the community is there's an interest in additional efficacy. That's been our mission all along. With an FGFR3 selective, we have the opportunity to increase the dose and the target engagement for FGFR3 to potentially achieve that.
We'll have the first readout of 6 months of our safety sentinel, which will have individuals, at least 3 at each of the doses, 4 doses, you know, at 6 months. That'll be a really important, you know, dose response curve that we'll be looking at to highlight the potential of FGFR3 inhibition further improving initially annualized height velocity as a surrogate, but of course, all the other clinical sequela that we're looking for. All 3 of these conditions are very well validated with FGFR3 as the driving target. Dabogratinib now, we've validated it in a phase 1 study to be a highly selective efficacious drug as we shared in our Triple Meeting data.
Once we get to 90 mgs, we have excellent target engagement with this drug, an ORR of 50% at 90, which is really comparable to anyone else's. If you think about erdafitinib, that's 35%. We know that we've got full target engagement there. What's important about that is we also know from that dose, the lower doses we can go into that are gonna be effective in Acon, that are gonna be effective in NMIBC. That has been so critical for our dose selection, and we're able to leverage some of the work that, again, both BridgeBio, J&J have done with erdafitinib to pick the doses and understand what are likely gonna be the effective doses. That's guided our phase 2 strategies and I think will help us have some winning data this year.
Great. Thank you very much for that overview. We'll start in the bladder with Dabo. SURF302, can you talk about how enrollment in that study has gone? As we think about this update that you're gonna give, can you help us understand how many patients that might be in the dosing, and then also what the expectation should be for the 3-month CR at this interim?
We've been guiding to 10-15 patients at each of our 2 doses. The first patient was actually dosed in the summer, and we only had a few sites open until the end of last year. We had a bolus of sites open up at the end of December. That's driven significant recruitment this quarter. Many of the patients are coming on study this quarter, so that 3-month endpoint is gonna be, you know, the majority of the patients. There will be, though, for example, the patient that was dosed in the summer, there'll be much longer follow-up for there to analyze with that particular patient. For the most part, this is gonna be a 3-month data point. It's really important to highlight this is a signal-seeking study.
We are not treating patients in the way that we would intend to treat them commercially. We're not treating them in the way that a phase 3 would be designed. What we're doing is leaving a small marked lesion behind, which is a big ask for a patient, quite frankly, and giving them drug and evaluating the dose that is effective in removing that lesion in at least 70% of patients or more. We wanna pick the most tolerable or, you know, the lowest dose that achieve that 70% CR rate or better. We've gotten that really from the KOLs and they're concerned about, I want to put a patient that can stay on this drug for years, so I can Don't have to do any intravesical, you know, treatments.
We, you know, we could say with very high confidence that if we treated patients with our 90 mg dose, we would expect a very high CR rate given the Thor-2 data set that we've seen. We also expect, just like, you know, J&J moved their dose down from 9 milligrams to 6 milligrams, us moving our dose down to 90 to 60 milligrams is a similar decrease in target engagement. It does improve the tolerability profile, you can see that from our Triple data, in a way that really is ideal. If we can get to more than 70% CR rate with the 60, we are even testing 50 to see if we can get to that CR rate, and potentially have the most optimal tolerability. That's the goal of the study.
Now, you know, a lot of investors ask us like, "Well, but we wanna see you look like Thor-2 at 89%. Isn't 95% better than 70%?" The most important thing to understand here is that we're not talking about the endpoint for the phase III. We're talking about estimating a risk ratio to apply to the phase III. The phase III for CG Oncology, for J&J, these are adjuvant studies. That means you remove the tumor, potentially give a chemo wash, and in a control arm, you expect 70% of patients may still be disease-free at 12 months. That would suggest there's only 30% of patients that are at risk. If we apply a risk ratio predicted from our phase II, where we're getting 70% CR, that would be a risk ratio of 0.3.
That means, you know, 1 in 3 patients are now recurring out of that, or a 90% DFS would be the expected outcome, which is an exceptional outcome. Going above 70%, you know, marginally improves you above 90%. Getting that most tolerable dose is so important, and we continue to reiterate that with investors because I know it's not intuitive, but it's what the KOLs want, and it's really what will help us design a successful Phase 3 study.
Okay. As you've shown in your deck and the data over the years, Dabogratinib is exquisitely selective, but maybe you could just elaborate on safety, right? Urologists, you know, they're used to intravesical therapies and not used to kind of therapeutics historically, or at least some of them, and they wanna see kind of really strong safety. What about the existing data gives you confidence at those lower doses that you should have a clean safety profile?
I mean, the data's out there for everyone to see. We had 22 patients treated at either 40 or 60 mgs. The majority of them saw 60 mgs. We had the rate of diarrhea was 18%. We had one ALT, AST out of that 22 patients. We really didn't see anything else of significant concern. As we move up into 90, we had, you know, very, you know, light reports of, you know, 2 patients with Grade one, you know, hyperphos. As we move beyond 90, you would expect to see more of that pan-FGFR activity as we hit those targets sort of next on the list. We have this really clear dose responsiveness. 90, you know, but for some increases in AST and ALT and diarrhea, was a really well-tolerated dose.
Moving down to 60, there were no discontinuations, no reductions, no hyperphosphatemia. The, you know, diarrhea was, as I mentioned, 20%, 1 grade 1 ALT event. That is an ideal safety profile for this population. Just repeating what we already seen in 22 patients would be ideal, coupled with the efficacy that we anticipate with the target engagement.
Okay. If you show that consistently clean safety and a 70%+ CR rate with the interim look, what's the path forward for Dabogratinib in intermediate-risk MIBC? How soon can you start a pivotal trial and get to market?
We would use the data that we anticipate sharing mid-year, you know, with a briefing book to go to FDA, justify a dose, and provide a phase III design that we would like to align on. That phase III design, we anticipate, would look a lot like CG Oncology's. With an oral, we have a unique opportunity to do a placebo. That's really advantageous both for, you know, proving efficacy, but also proving safety, and it's something with the intravesical devices you're not gonna do the sham, you know, placebo, that really hasn't been an option on the table. We think that's an option for us. We'd likely do a TURBT, chemo wash, and then randomize. You know, that's our sort of. We're not guiding to that yet.
We need to talk to the agencies, but that's sort of our going idea, and I think it's supported by what others have been able to get through and as they moved into phase III.
Okay. I think most people by now appreciate the broader intermediate-risk and MIBC opportunity given all the companies in the space. You know, in terms of uptake in urologist practices, do you think it's gonna be, you know, what factors do you think can drive physician uptake in these practices as a novel therapeutic option based upon what you've seen? Then also, how do you think about patient uptake, right? 'Cause that's another way to drive uptake of Dabogratinib in the setting.
Yeah. I'm going to ask you to undergo an exercise with me to answer this question, Tyler, for the benefit of highlighting the patient journey, which is really, really important here. I want you to imagine 40 years from now you wake up and there's blood in your urine. Call your physician, the physician says, "Yeah, you should probably see a urologist." You look up a urologist. You're gonna drive over 30 minutes 'cause your community urologist isn't gonna be that close. Show up in the office, the urologist is gonna lay you out on the table, and he's gonna put the catheter up through your urethra and then put this camera up through your urethra while you're awake and visualize and tell you, "Hey, look, I'm seeing some lesions.
Looks like you could have some bladder cancer. It's okay, we've got some treatment opportunities here. We're going to have you come back in 2 weeks. I'm gonna schedule you in my OR room, and we'll see you then. You go home with a cancer diagnosis, Google, you know, some panic, all of that, and you kinda wait 2 weeks before you show back up in the OR. Your wife gets a babysitter and I guess your kids are grown by then, drops you off at the OR room. You know, general anesthesia, so count down from 10, you're asleep, and then you wake up.
While you're asleep, the physician used these large telescoping devices up through your urethra with this hot wire at the end to cut tumors out of your, out of your bladder. Thankfully, he didn't nick the wall, so you wake up and you're not in the emergency room. He says, "Okay, good news, I was able to remove the lesions. From what I can tell, I'm pretty confident that could be lower grade and likely not muscle invasive, but I need to send all those tumors I just took off to path. Go home, rest, and I'll call you in a week when once I have the path report." Now you go home. You're still stressed. A week later, you get a call from the physician and the physician says, "Tyler, good news. Your path report came back, and they're all low grade.
Because you had multifocal lesions, it means you're in this category of intermediate risk. Now, the good news is we're not gonna need to remove your bladder. It's likely not going to progress or kill you. The bad news is this is a disease of recurrence, and there's a one in 3 chance, no matter what I do, you're gonna be back in my office within the year, going under general anesthesia, and putting those devices in to pull the tumors out. 2 options for you today, standard of care. We can just watch and wait, come back in 3 months. If the tumors are back, we'll schedule you for the TURBT. If you wanna be more aggressive, we can schedule you to come back next week, and then every week thereafter, we're gonna install the catheter again.
We're gonna push chemo up into your bladder, and we'll have you lay on the bed for a couple hours to just try and keep that exposure and spread out a bit.
A couple hours?
Potentially a couple hours because the longer you let it wait, you know, the better chance it's going to keep you tumor-free. You hold it as long as you can. You use up a ton of office space. Quite frankly, as a physician, I'm not excited about these relatively inexpensive chemo, these procedures, and all the staff time that's doing it, I'm not necessarily gonna encourage you to do all that. Some patients really wanna make sure they get all these installations because, you know, it could help. You do that, you know, every month thereafter. At the end of 2 years, 30 installations. That is standard of care today. That's what those are the options that patients have, watch and wait or all those installations.
In the future, you know, we might see some uptake of UroGen, which is kinda keeps you from having to wait a couple hours 'cause they can install the chemo gel, and it sits around a little bit longer. We could have a viral vector from CG Oncology. You're still gonna do every visit 6 weeks after, put the viral vector in your bladder, do it every quarter thereafter. It's not really changing it, but maybe you don't have to wait 2 hours 'cause the viral vector's a little bit faster. If TAR-200 gets approved, we can invite you back in a week, put the device up in your bladder, tie it in a knot, and we don't have to do anything for 3 months. You're gonna feel it. You're gonna feel like you need to pee. You're likely gonna get a UTI.
You know, we'll switch it out every 3 months and give you general antibiotics. If we're successful at Tyra, if, you know, folks invest in us and we successfully execute the phase 3, there will be a future option where the physician will say, "I can drop ship you a drug. It'll be on your doorstep in the morning, and you just take one pill a day. I'll see you in 3 months. You know, this has been a proven treatment to reduce the likelihood you're gonna be back in my office, and you won't need to do all these intravesical treatments or surgery." That's a game changer for a patient, and it aligns with the physician's practice in the sense that they're not looking to do all these cheap procedures with their staff.
Where you're getting treated, where 80% of patients are getting treated is in the community. In the community, all of these physicians have already set up, you know, nearly all of them have set up in-office dispensed pharmacies which allow them to prescribe oral prostate cancer drugs. Because of that pharmacy that they've set up and licensed, they participate in the economics. It's a major driver of the economic revenue in their practice, and it allows them to choose orals over procedures because neither is gonna make them more or less money. Both of them have a spread that they can enjoy. Procedures buy-and-bill gives you about a 4% spread on the drug.
With the in-office dispensed pharmacy, they can get the same benefit, but they don't have to force their staff into doing this or the patients into doing procedures over oral. Those dynamics I think are gonna be really, really favorable for an oral drug. As we work with, you know, the community and talk to KOLs that are aware of what we're doing, we're definitely seeing that enthusiasm grow.
I'll try the pill first. In terms of the economics, what practices are currently set up with the internal pharmacies to capture those economics? Can you talk about, you know, penetration of therapeutics in these practices in general across therapeutic areas today?
Yeah. About 80% of practices in the community work with UroGPO, a division of Cardinal Health, that sets these up, and they've been doing it for the last 15 years for prostate cancer drugs. It's pretty well entrenched at this point. One important point that I think is good to make for some of the investors listening is if you, if you were to call up the urologist at MGH, he's gonna tell you a little bit of a different story than I just told you. In the academic medical centers. Their urologists are not doing oral prescribing. They're sending the prostate cancer patients over to Med-Onc. The hospital in many of these places has allowed them to take the buy-and-bill revenue. They have an incentive to do the procedures.
A lot of investors say, "Hey, I just talked to a KOL, and he tells me, like, they like procedures more than this." That could be true in 20% of the market where patients are treated, places like MGH or MD Anderson, but the majority of patients are treated in the community. It's really important that when you do a KOL call that you at least talk to a few folks that are actually doing this, you know, KOLs that are doing community practices.
Before we go to achondroplasia, we should touch on upper tract, which you mentioned. You know, previously some folks were expecting you maybe to continue pursuing the metastatic setting. Maybe again, you could just elaborate on why you chose to switch to upper tract, you know, what the pathway to potential approval could be there, and again, what you view the opportunity to be?
You know, this is a simple exercise, an internal exercise around prioritization. You know, we do NPVs and models just like investors and try and, you know, use the precious cash that we have in the most, you know, fruitful way. This was a really clear answer for us. You know, MUC, a high unmet need indication, but really, you know, differentiating in that setting, you know, without thinking about triple combos and really prolonged studies and a lot of money and kind of marginal benefit, was not nearly as attractive as what we saw as the unmet need we could potentially address in UTUC. For one, the FGFR3 positivity is 80% plus in low-grade UTUC versus the 15%-20% in metastatic. We analyzed this.
We actually had a physician at MD Anderson reach out to us and ask us about running this study, Surena Matin. He was the number one prescriber of Jelmyto and, you know, he had actually worked with infigratinib in this setting as well and seen really good results, but patients couldn't stay on the drug 'cause of the tolerability issues. He said, "Look, I saw your MUC data. I really wanna run a study." That caused us to really evaluate it further, and when we did the market research, it became really clear.
While it's a rare disease, about 3,000 patients a year, the experience of this patient, you know, take everything I just told you start with the blood and the urine, but this time when you go in, you don't see the lesions in the bladder and on follow-up, maybe CT, you see some lesions in the, in the ureter or the kidney, you know, urothelial lining. Now you're in a really tough situation because you can't use that large telescoping device.
Thank goodness.
Well, you don't wanna see what they have to try and use. They've got a really thin device that they're gonna try and stick up the ureter to remove tumors, and it just is not very effective. You could also, you know, bore into the back from behind and then try and use those large telescoping devices through the back, after you've dug, you know, put the hole in and you can remove some tumors that way. Or you can put a nephrostomy tube in the back and try and put the chemo gel from Jelmyto. What I'm painting here is this is a really awful situation. As a result, the physician I spoke to last week told me he thinks maybe 40% of patients on initial diagnosis just have their kidney removed.
After trying some treatments and removing it, recurrence is really high, and patients end up getting their kidneys removed then. We're talking about a massive unmet need, potential future dialysis, kidney transplant. These are real big issues, and there's just nothing good you can do about it. At 80% FGFR3 positivity, this is just a no-brainer. It takes us 30 seconds to talk to a KOL before they're just completely sold on the study. Really big opportunity. The last piece here is that this is the registrational path for Jelmyto was a 70-patient single-arm study. Last summer, when UroGen had their ODAC, FDA referenced that and said that that is an acceptable path for this indication, single-arm patient study. It's actually on FDA's slide.
We feel really good about the registrational path. The study that's now open, the phase 2 study, it's Part A is dose selection, but it's Part B has registrational intent. It's actually just an expansion just like the Jelmyto study. That allows us to potentially move very quickly here. It's a really concentrated set of centers where these patients are treated. Pavash, who's here with me, who's launched rare disease drugs, you know, he assures me that with a relatively small, you know, sales force, we can address these patients very broadly. Pricing, you know, we would expect to be in line with, you know, sparing the bladder-sparing approaches like A-Activa and the J&J drug. You know, great opportunity for addressing unmet need.
Patients we anticipate would wanna stay on this drug to keep their kidney. From an incidence population, we could see this kind of move into a prevalence-type population like a Gleevec. This all, you know, comes together to highlight for us a, like I said, blockbuster, billion-plus opportunity, and our first-to-market opportunity with the drug.
Yep. Jay?
Is the bar for this for Upper Tract lower?
Absolutely lower, yeah. When we tested market research, we looked at, like, CR rates less than 50%, CR rates more than 50%, and it did not change the intent to prescribe, which was, you know, the majority of their patients they would wanna put on this drug. Of course, we wanna optimize the CR rate because it means, you know, more patients will save their kidneys, stay on drug longer. We are looking at a higher dose than NMIBC for that reason. Because you're, you know, you're gonna have leftover tumor, potentially bulky tumors. We'll evaluate whether there's a difference at 60 or 80 mgs in this setting, and we think that there could be a little bit more of a tolerance for 80s as well.
That's the differential dosing strategy for UTUC as well.
All right. You certainly sold the unmet need given the patient experience, and it makes sense as to why investors are so excited about your approach in bladder across these 2 indications. We got to spend time on achondroplasia, which has been a big focus historically for you all as well. We'll have the Sentinel cohort update in the H2 by the end of the year. Maybe you could first start by talking about what your thoughts were post the BridgeBio infigratinib PROPEL 3 data that were reported recently. What is the window of opportunity remaining following that data for Dabogratinib? With the Sentinel cohort data, what you will be able to show to potentially suggest that you can address that window of opportunity.
I mean, first off, really excited by the data. You know, congrats to BridgeBio, to everyone that participated in that study. This is gonna be a, we think, a great option for patients. It's an oral. Hasn't been an oral in this community. It's delivering the type of efficacy you can see with CNPs, which does have a, you know, a meaningful benefit. Great outcome. I think we expected the safety profile that they saw. I haven't seen the full AE tables, but just from what they described, it appears to be safe, and that's what we would anticipate as well because they've chosen that dose right before they anticipated seeing hypophosphatemia from their phase 1. Great results across the board.
The key thing here is, you know, investors ask us, is there efficacy left on the table? There absolutely is. There's a couple of ways to articulate this. One is we have a lot of patients on Voxzogo coming to us 'cause they're just not seeing the efficacy wanting to get on the study. There's patients that are on Voxzogo getting limb lengthening surgeries, you know, largely in Europe, 'cause they're looking for more efficacy. You know, when we look at what would be a typical what could truly restore like typical height, like really, change the physiology of the FGFR3, the difference between an adult male with and without achondroplasia is, you know, 196 versus 130 centimeters. It's a 46 centimeter difference.
You have 17 years of active growth plates if you're a male. If you divide 46 by 17, the difference is 2.7 centimeters every single year. That's the incremental growth you wanna get if you truly want to get to a typical height. Same calculation works in females. It's a smaller height difference, but you just divide by 14 the amount of years that you have the open growth plates as a female. 2.7's really that number. It's an extra centimeter on top of the 1.7 that BridgeBio just showed and the similar 1.6, 1.7 that you're seeing with the other CNP agents. We've got a really clear idea of what we want to accomplish here.
The other thing about the data that was great was it really fit exactly into our model where we think their target engagement should have delivered. We know that full target engagement can deliver, and we see this 19 centimeters per year growth. That amount of growth causes fractures and real challenges. That's 8 inches a year. That's a significant amount of growth. When you start to look at that model of target engagement, it's really clear for us the doses now that we wanna get to that should get us to a meaningful increase in growth, potentially to the, to the target. We are confident that the doses that would do that, we're sparing FGFR1 too, so we don't have the hypophosphatemia, the restrictions on dosing up.
That's exactly what that, what the study will, you know, reveal. It's the Sentinel doses one, 2, 3, and 4, that will all read out at 6 months. We're looking for a dose response curve there in the data that essentially says, yes, as we get to the higher doses, we're outperforming what other agents have seen at 6 months in terms of AHV as really strong evidence that we're hitting the target the way that we anticipate that we are.
Great. Again, just to confirm, it's gonna be an increase in AHV from baseline, right? You won't have a lead in like you would in a registrational trial. You'll be able to see the increase in AHV. We'll be able to look at that annualized and see whether you're able to get them to 7 instead of 6 on an absolute.
Yeah. No baseline, so it's a dose response of AHVs, right?
Yeah.
At your lowest dose AHV to your highest dose AHV, what's the response curve suggest, right? At the higher doses, you would wanna be well above 7 centimeters of annualized height velocity, which is what the, you know, the 6.8 was kind of the highest number we've seen from BridgeBio, that CNPs were in the lower 6s. Yes, we wanna be getting into the 7 and above with those kids that are treated at the higher doses.
Okay. Are there any other secondary endpoints that you all will be reporting on at this stage, or do we need to wait for future readouts?
Yeah. I mean, obviously, there's not anything placebo-controlled, but we can look at all the things that we'll measure. You know, we're looking with radiography, things like tibial bowing, we're looking at proportionality. Those are things that could all be moving in a direction that gives us like really strong encouragement for the design of the phase 3.
Okay. What do you need to start the phase 3? What data do you need from this phase 2 study to start the phase 3 and potentially get to market?
You know, most other agents have looked at kinda 10 kids at the right dose level to be confident. You know, the safety sentinel is not gonna be 10 at each dose. It'll be more than 3 is sort of what we're guiding to. That will also then be supplanted from our cohorts 1 or supported by our cohorts 1 and 2, where kids will be coming off the natural history portion and starting to get on doses where we can measure PK, evaluate safety. You know, we're looking to kinda get to that, you know, 8 to 10 children at a dose where we feel confident on safety.
We've got 6 months data, potentially some of the patients converted into 12 months data, you know, to be able to leverage that with FDA and kick off the study.
Great. Unfortunately, we don't have time to cover 430 in HCC or 200 in ICC, but, you know, since we're up on time here, Todd, to close out, maybe we'll just ask you what you believe is the most underappreciated aspect of the Tyra story by investors.
Yeah. I think our internal projections of the opportunity across all 3 indications here, I think exceed, no offense, but the general analyst expectations of, you know, that are out there. I think many investors are asking us questions about like how exciting and how big this can be, and we feel very bullish on the TPP that we've highlighted, right? The promise of oral Dabogratinib can generate a really incredible opportunity by hitting the unmet need and a very meaningful revenue potential for the drug long term.
We're just trying to ratchet our estimates up over time, you know, give you some space. With that, Todd, thank you so much for your time. Thanks everyone for being here. I believe it's lunch, so we'll go ahead and wrap up.
Thanks, Tyler.