Everyone, thanks for joining our virtual Conference. I'm Matt Biegler. I'm the covering analyst for our next company, which is Tyra. We've got Todd Harris, CEO here. Todd, always nice to see you.
Great to see you, Matt. Thanks for having me.
You know, it's been an exciting time for you guys. dabogratinib, one pill, many uses. It's been fun to see the story evolve. You started in metastatic bladder cancer, now we're looking at earlier stage bladder cancer. We're looking at bone growth disorders. It seems like there keeps being new indications that you guys are finding this drug can be used for. Just maybe for those that don't know the story, kind of like walk us through what are the lessons that you've learned so far from dosing patients, and kind of where do you see yourself, you know, into next year?
Yeah, it's a great setup right now for Tyra. We, you know, through a lot of effort, we've really focused in on our highest value opportunities that have very strong validation, where FGFR3 is the driver. That includes, you know, two in urothelial, the low-grade upper tract urothelial carcinoma, and the intermediate risk non-muscle invasive bladder cancer, and then the lead indication in skeletal dysplasias, which is achondroplasia. What unifies all of these is that either constitutively active FGFR3 alterations in the case of somatic mutations in bladder and urothelial, or overexpressing FGFR3 alterations in the case of skeletal dysplasias, including achondroplasia. You know, that is the target, and it's really well-validated and unbelievable data that J&J's been able to generate over time with erdafitinib.
That's validated that in both early and late-stage diseases, now great validation coming out of excellent data we saw from BridgeBio with infigratinib on the achondroplasia side. Then you highlighted this, Matt, which is just we have our molecule, dabogratinib. We've run a phase I in the metastatic setting, really proving what we hoped we could see, which is the alleviation, the significant reduction of any FGFR1 or 2-associated toxicities by making an FGFR3 inhibitor. I think we also had this real benefit of also seeing diarrhea go much lower than the one other drug that's also out there attempting to do this from Loxo. Those things opened up the opportunity to do what others have not been able to do in these indications with the pan-FGFR inhibitors.
Yeah.
For, you know, the low-grade diseases, erdafitinib demonstrated they were highly responsive to low doses of erdafitinib. The toxicity profile was not satisfactory for a systemic drug. They put it in the pretzel to do local delivery. Systemic, you know, oral approach, and we can talk about this, we still think.
Yeah
... Is a total game changer.
Yeah.
On the side of achondroplasia, you know, efficacy in line with the CNPs is what we're seeing with oral infigratinib at the very low dose, and we've said for a very long time now, if we engage the target further, we anticipate improved efficacy. We think there's a whole centimeter of additional growth that the community would love to see that could read through to all of those other important clinical sequelae, and that is highly achievable with a selective drug because of the window, therapeutic window relative to hyperphosphatemia and the FGFR1 and 2 associated tox.
It's, it's nice to see the whole hypothesis of the company really come to fruition, right? Which is that if you have a very, very selective FGFR3 inhibitor, you're going to spare those very well known and characterizes toxicities from the other isoforms. Now that you're embarking into non-muscle invasive bladder, into achon bone growth, you know, risk to benefit is really important here, right? Because it's not like metastatic urothelial, where you have, you know, 6-12 months to live. I think everyone's kind of still a little bit worried about, like, "Okay, is there going to be some kind of idiosyncratic tox here that's going to torpedo the whole program?" I think I wrote down in my last notes that you've dosed now over 100 patients across your different programs. Where do you kind of sit on safety?
Yeah, it's not just the 100 patients that have touched the drug. You know, you also, to get here, because this is chronic dosing.
Yeah
... You need, you need your, you know, multi-species chronic toxicity studies complete, you know, reproductive toxicology studies complete, phototoxicity, genotoxicity, you know, QT interval. All of these preclinical, you know, boxes you also have to check. You know, you don't even check before you get into, you know, a phase I oncology, you know, study. Those are things that were also happening alongside of our metastatic phase I data collecting, and we're all, you know, key for us moving forward. Those all build our confidence in the profile of the predictability here, of the drug, and it's well-behaved, it's got well-behaved PK. You know, with each patient and with each of these studies, it ultimately reduces the risk of idiosyncratic talks.
Yeah.
The data set that we put out there with the triple meeting about a year and a half ago, I mean, it really highlights that the doses that we're using alleviate even the AST, ALT increases seen at the higher doses, which are asymptomatic. There's a huge dose response curve when we went from 60 to 90. Yeah, the only real main signal showing up at the highest doses for the, yeah, that we're really covering the target for the metastatic, that was the 90 mg, was the, you know, some diarrhea and AST, ALT. To see the AST, ALT go away, almost completely, low-grade diarrhea, you know, if we're still seeing it's going to be low frequency, low grade.
That's, you know, probably the most likely thing we would see, but it's very addressable here. It's, you know, the alternative to that in terms of urethral violations, you know, is far more severe. If you look at just the toxicities associated with things like ZUSDURI and Inlexso.
Yeah.
There's a lot of other things these patients are worrying about than potentially that. It gives us just real good confidence. We've got work to do. We gotta obviously execute, and we need to do that fine balance of dose selection. We're feeling really good that we have a drug here in all three of those indications that we highlighted.
I think I'll take some low-grade diarrhea over a UTI any day. Just me, you know, keep it regular. Let's start with achondroplasia. You know, it's topical because of the PROPEL-3 data that we saw a couple of weeks ago from Bridge. You know, you kind of predicted it in terms of, you know, what we would see from an HV perspective. The data, I guess, were pretty in line with what you thought?
Yeah. I mean, for us, this is a Goldilocks dataset for us. I think it's a Goldilocks dataset for BridgeBio, and we're, you know, really rooting for their success on an approval and delivering an oral therapy for these kids that get them to the type of analyzed height velocity and benefits that the CNPs have seen. That's, you know, that's all great news, I think, for everybody here, right? And we can celebrate it. We've been consistent for a very long time, saying that we anticipate, based off of their target engagement, that this is about the result they'll see.
There's a, you know, there's another centimeter of additional growth every single year you would want if you truly want to restore the type of analyzed height velocity that could get you to a final adult height of, you know, someone that doesn't have the alteration. With that comes what we really hope for, is the clinical sequela benefits, the benefits in reach, potential endurance. You know, when we talk about reach, it's things like: Can you wash your hair in the morning? You know, how well can you toilet yourself? You know, some of your daily adaptations in life, driving a car, right? When you talk about the sort of endurance piece, it's just, you know, there's a lot more required to get upstairs and to do, you know, various things when you have disproportionate short stature.
When we talk about real risk of outcomes and things that lead to shorter lifespan, you know, it's things like the spinal stenosis or the foramen magnum stenosis that increase sudden infant death syndrome, that increase the need for surgeries over time, and make it more challenging to live with the condition. That's what matters, and of course, you want to engage FGFR3 in the way that, you know, removes the alteration that's giving the negative signaling, you know, to fully reach those potential benefits.
Remind me of the doses that you're testing now in your BEACH301 trial, and kind of how does that compare to what was tested in the metastatic setting?
Yeah. In the metastatic setting, we had a great outcome in terms of ORR. It was 5 out of 10 patients that responded at 90 milligrams. We typically compare that. you know, our modeling suggests that that fully covers IC90. We look at that 90 milligrams as the dose of full target engagement to get to the best outcomes you can get to in the metastatic setting. You can compare that to Erdafitinib's 35% ORR and say, "We're doing the best we can with 90 mgs for that particular disease setting." Now, when we think about achondroplasia, there are case studies of children that have gone on these, on these full oncology doses, including Erdafitinib, where you get this full target engagement.
During the time they're on that drug, they're gonna grow 19 centimeters per year. That's 8 inches a year. It's exorbitant growth, and it comes with the risk of fractures and other issues. I highlight that because, 1, we know we don't want to use a 90 mg dose in these kids.
Yeah.
It also gives us a predictable way to evaluate what doses should work.
Mm.
You know, we now have two great data points. We know that at full target engagement, with an FGFR3 inhibition, you've got 19 centimeters per year. With one-sixth of the dose of that full target engagement, BridgeBio just showed us you can get to 6 centimeters per year. Yeah, it's a fun exercise. Draw the curve or the line between doses to anticipate what might you be able to do. When we've done that, we feel very confident that all the way up to our 40 mg adult dose, that gets to us to about half of the, you know, IC50 coverage on average, could be safely administered and could give quite, you know, exceptional growth. We're testing, you know, we're testing our 10, 20, 30, and 40 mg dose equivalents in the adult, in the kids.
Okay.
That translates to the, you know, divide by 80 kg. You know, it translates to the 0.125, 0.25, 0.375, 0.5. That's really the spectrum we believe preclinically we want to be. It's also genetically validated.
Yep
in the sense that there are individuals that have, You know, if you're born with a double allele knockout of FGFR3, it's a lethal phenotype. You know, you can't sustain that eight inches of growth every year, right?
Yep.
A single allele knockout is tolerated, and individuals grow on average about 6 foot 5 or 20 centimeters taller than the typical. That's a nice proxy for, you know, you can, you can get relatively good bone architecture with no significant complications.
Yep.
That's driven by cutting FGFR3 expression in half. You know, that's kind of where our 40 mg dose could potentially go to, and we feel that's probably the upper bound of where we should be testing.
Gotcha. Should be interesting to see. You're now enrolling BEACH301. There's a safety sentinel cohort. We'll get some data from it this year. It's not gonna have a natural history run-in, so, I mean, can we look at that data and try to compare it to what we just saw from Enfortumab?
Yeah. Yes. Look, if we hit the efficacy that we anticipate, you're gonna see a very nice and clear correlation or dose response in this, in this data set, even at a, at 3-plus patients per dose. That's gonna be key, and we've highlighted that target engagement at our second dose should be maybe modestly better than enfortumab, but at our third and fourth dose, should definitely exceed the target engagement of enfortumab. You can take those 6-plus kids and really look at the 6-month AHV data for the competitive drugs in their phase 2s and say, "You know, are we doing better?" All of those data sets came in in the either low to high sixes, so like 6.2 to 6.8.
What we're gonna be looking for is something that's, you know, in those top, you know, one or two doses, really getting into 7 centimeters, and more potentially. That would be the signal that, yes, the thesis, you know, that we've articulated, further target engagement will push the growth beyond what others have seen.
Should be really exciting to see. Just because of for time's sake, let's kind of dive into bladder cancer now. For those that don't know, just why the initial focus on intermediate risk and not high risk? It seems like most of the development, if you think about CG Oncology, some of the other intralesional ones have gone high risk. They're now shifting into intermediate risk. They, like, used high risk as proving ground, now they're shifting into intermediate. Why is an oral option FGFR3 better for intermediate?
Yeah, you know, it's all about the underlying genetics.
Sure.
Where FGFR3 is the driver is in low-grade lesions, low-grade intermediate risk lesions. You're gonna see, well, north of 70% FGFR3 positivity if you just focus on the low-grade lesions in the intermediate risk setting. That's 35,000, you know, new patients a year showing up with that genetic alteration. I think it's important to highlight a point, which is, when that happens, when you get the somatic mutation in your urothelial cell, that, you know, unfortunately, you get the TACC3 fusion or one of the four cysteine mutations, what happens then is you start growing out low-grade lesions. It's not sufficient to drive invasion and metastases, right? That's and the progression of these low-grade lesions is actually pretty low, the percentages in the single digits.
You're not likely to see this progress and kill you in 5 years. That's an important, really important point because when you look in high risk, that FGFR3 positivity goes down. It might be more like 30%-40%. When you look at metastases, it goes down to 15%-20%. Why is there a selection bias away from FGFR3?
Yeah.
You know, my hypothesis really, that you need the other co-mutations and alterations to generate those higher risk phenotypes. As a result, their responsiveness to FGFR3 inhibition is not as strong, and you see this in the erdafitinib data. You go into the metastatic setting, it's a 35% ORR at the, their full target engagement. They can drop the dose and get an 89% CR rate.
Mm-hmm
In the intermediate risk setting.
Mm.
That alone tells you that the right condition and disease to treat with an oral FGFR3 inhibitor is those high, you know, high prevalence FGFR3. It's the intermediate risk NMIBC setting. That's where the patients are best, most likely to have an excellent response and then keep those lesions from coming back. That's why we're focused there.
Mm-hmm.
Yes, we could look at high-risk FGFR3 positivity, some of these other areas, but the standalone largest indication, the most patients that we could benefit, is gonna be in the intermediate risk setting.
In that setting, the benefit is really just to reduce the need for these costly, time-consuming, and invasive TURBT procedures, right?
That is exactly right, it's such an important point, urethral violations. Even if you listen to, you know, FDA's ODAC for UroGen recently, which got the first approval in the intermediate risk setting in a very long time.
Yeah
... It's all about the burden of treatment, right? You know, I like to, you know, highlight this patient journey for folks. Matt, if you'll allow me, I'll use you as a case study here. You know, I want you to sort of imagine 40 years from now, because bladder cancer is not gonna happen probably too soon for you. It happens later. You know, one day you wake up and, you know, you've got blood in your urine, and that's obviously not. That's a daunting realization, so you call your physician, and they refer you into a urologist, and you drive over 30 minutes to your community urologist. That urologist is gonna put you on their table, lay you down, and they're gonna take a catheter up through your urethra and put a video up there.
You'll be awake, and in real time, the physician might say, "Okay, I'm seeing some what looks like low-grade lesions.
Yeah
Bladder cancer," right? We've got an opportunity to remove these surgically. You're gonna have to come back, and we're gonna do it under general anesthesia. You go home, and you Google, and you're pretty freaked out. You now know you have bladder cancer, and but you show up a week or 2 later, and you lay on the bed, and you go to sleep. You wake up, and there's these large telescoping devices that have now been put up through your bladder with a hot wire loop, that coil that's used to just snip out any tumors.
Yeah.
You'll wake up, and the physician will say, "Matt, everything went great. All your tumors are gone.
Yeah.
Next step for us, we're gonna send these off to path.
Yeah.
We do FGFR3 testing as well. You get a call. You know, but you go home, you recover, you get a call a week later, and, you know, the physician will say, "Hey, look, good news. Path said your lesions were low grade.
Yeah.
The challenge, though, Matt, is that this is a disease, no matter what we do, 1 in 3 patients is gonna come back in 12 months, and they're gonna have more tumors, and we're gonna have to go through this process again and cut it out.
Yeah.
Today's standard of care gives you 2 options: We can just watch and wait, and you come back every 3 months, and we'll scope you and see if the tumors come back, and then we'll TURBT you when it does. We can try and be more aggressive, and maybe it could help a little, and we'll install chemo in your bladder every week for the next 6 weeks. You come in, you lay on the table, we push the chemo in your bladder, you roll around for a couple of hours, and then we'll do it every month after that. At the end of 2 years, you've had 30 urethral violations, and you still might have a recurrence. That's standard of care today.
Yeah.
It's costly, and it's incredibly burdensome. It's quite embarrassing.
Yeah
... Patients don't want to talk about it a lot.
Yeah.
You know, the game-changing nature of this oral therapy is that a physician can say, "I've got a new option for you. I'm just gonna drop ship you dabogratinib. It shows up on your doorstep in the morning, you take a pill a day-
Yeah
... Your, you know, recurrence risk will go way down. We'll just continue to monitor you." That's what we're looking to do. That's the potential for the opportunity we're pursuing here.
Yeah, say what you want about ZUSDURI. I mean, they did not great clinical execution, but they did show, at least at a high level, that if you have that initial 3-month remission rate, that does translate downstream to reduced TURBT procedures, right? I think that that's why ZUSDURI ultimately was approved. Would you agree?
Yeah, it does. It's a replacement for TURBT. It's an option, you know. It wasn't any worse than TURBT. I think that's an important setup as well, is we're looking for treatments that reduce recurrence, that are durable, and, like, just reduce the treatment burden on the patient.
Yeah. Yeah. I do get questions on: Why would a physician want to prescribe an oral where... I mean, the J code must be so great for these TURBT procedures. They must make so much more money from doing the procedures. Why would they ever want to prescribe an oral?
You know, there's a really good answer for that. The key is you want it, where 80% of patients are treated is in the community urology practices. With the advent of oral prostate cancer drugs, you know, the same question was asked, like: "Why, why should I do this oral drug when I can make money on procedures?" As a result, Cardinal Health's UroGPO helped set up oral dispense pharmacies in nearly 80% of all these practices so that they can participate in the economics of an oral. Many of these community urologists are making upwards of 40%-50% of their revenue from oral drugs successfully. Thanks to that model that's really grown out over the last 20 years, it's a model that we can fit right into out the gate.
If you talk to an oncologist at an academic medical center, they're not doing the oral prostate cancer drugs, and they will say: "Yeah, I don't you know, I just do procedures, so this is gonna be hard for me." That's only 20% of really where patients are actually going, and it's important to know who you're talking to and to make sure you make that distinction.
Yeah. I mean, you know, you've got CG, they're running their own kind of randomized trial. I'm envisioning, ultimately, this thing gets approved, 'cause as we talked about, the value prop here really is reducing TURBT. Ultimately, the FDA is probably gonna want you to show, in a randomized fashion, that you can reduce TURBT. I think the data that you're gonna have this year is important from showing complete remission. Maybe just kind of set some guideposts for what you hope to show from that data set and why you think that then will go on to translate to reducing TURBT procedures?
Yep, great question. It's important to recognize we're running a phase II that's signal-seeking, and it's not designed like what our phase III would be or what CG Oncology and TAR-210's phase III are. We keep a little tumor, a little window, sorry, a little marked lesion in the bladder, ask the patients to keep, you know, keep that in, take the drug, so that we can show it gets removed. If it goes away, it's a CR. What we're looking for is a CR rate of 70% or greater with excellent durability, but we know the durability should be strong already because of the THOR-2 data, as long as it's well-tolerated. Our benchmark is, we wanna get 70% or greater CR at the most tolerable drug. That's gonna translate to an excellent DFS rate in a phase III.
You know, we have to estimate that. The disease-free survival rate on a placebo or observation, probably gonna be at about 70% are gonna be disease-free. What we're looking to do in the 30% that aren't, to obviously, you know, keep any tumor from showing up.
Mm-hmm.
If we're getting a 70% CR rate with great durability, the landmark CR, you know, is close to 70%. That means that 21 out of those 30, you know, 21% out of that 30% should be disease-free if the drug is working. That's gonna be 85%-90% DFS. That's what we power the study for, that's what J&J's powered their study for. That's essentially what we're looking for, marginal differences between 90% disease-free survival, or 91 or 92, are not as important as just maintaining an excellent tolerability. Anything north of 70% CR gets us that estimation and would be, you know, essentially the TPP we're trying to hit.
Let's finish up on a newer indication that you've recently discovered or at least announced publicly, UTUC, here. You're not trying to reduce TURBT procedures, you're actually trying to spare kidneys because TURBTs don't work. I mean, this could enable a potential for an accelerated route to approval based on something like a complete remission rate. Can you just tell us a little bit about UTUC and kind of the unmet need there?
Yes. Unbelievable unmet need here. I mean, the physician I was visiting last week, I asked him, "You know, of the low-grade, UTUC newly diagnosed patients, how many are going to lose the kidney?" His estimation was about 40%.
Wow.
Right? This is a disease that's not necessarily going to kill you, but you're starting to have your ureters and your kidneys fill up with the same lesions that are in the IR NMIBC setting. They're on the urothelial lining, but now they're just in a really inconvenient location.
Yeah.
You know, if you don't lose your kidney, you're talking about things like putting a ureteroscope up through the ureter, trying to remove things. It's very hard. Drilling a hole in the back and putting the same kind of telescoping devices you put in the, in the bladder through the urethra into the kidney to try and, you know, cut out tumors. As you can imagine, it's not effective. It's not very effective, and these things come back, and patients typically lose a kidney. Gemcitabine is used, again, you're, you know, basically putting a tube through the back of the kidney and trying to deliver this. It's not, you know, there's just not good treatments. This would be a game changer, right?
Oral treatment to, you know, have those tumors go away, to spare your kidneys. If that kidney's spared, you know, the idea of kind of staying on the drug so that you can avoid having to lose your kidney, becomes very compelling for a patient. Even though this is a rare disease, 3,000 patients a year, you can imagine over time, this becomes more like a Gleevec opportunity, where the population benefiting just builds and builds as you spare the kidneys.
SURF303 trial in UTUC is expected to kick off soon or has already kicked off?
Expected to kick off soon. We have the IND clearance. Importantly, this is a study with registrational intent, we're kicking off the Part A, but the Part B is the single-arm expansion that's consistent with how UroGen got gemcitabine approved, and what that was validated again by the FDA in this past summer, and in the ODAC meeting, would be an acceptable approach for this type of indication. We could really get there to the market with this study. As soon as we start enrolling patients, we'll obviously seek to move it forward quickly. The primary endpoint would be that initial CR. That was the primary endpoint for gemcitabine, but of course-
Yeah
... We'll also want to show that work around how beneficial it could be to stay on drug.
Awesome. Just kind of wrapping up here to summarize it all. 4 open trials, right, by my count? SURF301, SURF302, SURF303, and BEACH301 in ICON, right?
Yep.
Data coming mid-year for NMIBC, later this year for ACH?
Later this year for ACH, yep, second half of the year. We'll guide to UTUC data when we have it. We're gonna finish that mUC study. Eventually, we'll publish, you know, a Phase I paper, but we're not continuing or spending cash to go into Phase II there because we think these opportunities we've articulated are really far more valuable. Certainly, that's an option in the future, but really, it's the focus is moving the Phase IIs that are open forward now.
Obviously, you've got your hands full with Davo, but are there any I mean, just based on all the learnings you now know from FGFR3 and the complexities of that protein, any other options for future pipeline projects you're looking at?
We keep a very active FGFR3 discovery program here at Tyra, you know, we want to be able to continue to innovate. There's potentially other indications. We also look at other targets, we have brought 2 other drugs into the clinic that are also, you know, potential value-creating over time. There's so much value in FGFR3, we, you know, we want to just remain and keep our leadership, both with Davo and, you know, any other novel drugs that can be made as we go along.
Yeah. Always fun, Todd. Congrats on the progress.
Thanks, Matt.
Thanks, everyone, for joining in.