Hello everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst at HC Wainwright. Today, I have the pleasure of welcoming Todd Harris, the CEO of Tyra Biosciences. Todd, thank you so much for joining us today.
Thanks for having me, Mitchell. It's great to be here.
Great. Maybe just to set the stage for those who may not be up to speed with the story, just give an overview of Tyra Biosciences, the different programs you're working on, and the key initiatives that Tyra Biosciences is working on today.
Sure. Tyra is a company. It's a precision medicine company that's largely focused on FGFR biology. We do drug discovery, drug development, and actually all of the compounds that are in the clinic we've made in-house through our SNAP chemistry platform. Our lead drug is an FGFR3 selective inhibitor. It's actually the first one to make it to the clinic. It's differentiated in that there have been pan-FGFR inhibitors that have come, and they're actually approved for a number of different indications. A truly selective FGFR3 inhibitor is a very challenging chemical matter to make, and it's one that we were able to conquer with our platform. Why is that important? There are actually some really compelling indications that are driven by FGFR3. On the side of bladder cancer, about half of all bladder cancer is driven by an FGFR3 mutation.
Especially in the early stage non-muscle invasive bladder cancer intermediate risk, where the majority of patients are, FGFR3 positivity is 70% plus. This is an area of really high unmet need. It's not necessarily a situation where overall survival is at risk. Most patients are going to live, 95% of patients are going to live in five years with this. It's a disease of really high surgical and interventional burden. Patients' standard of care is a surgical procedure under anesthesia to remove lesions, followed by chemo instillations. A friend of mine actually, who has the very condition that we're looking to treat in intermediate risk, talked about over the last two years since his diagnosis, he's actually had 36 catheterizations. Many of these are, you know, it's not just a 10-minute exercise.
You go into the office, you're catheterized, and then you spend four to six hours while chemo is being installed in your bladder, and that's every single month. There are a number of groups that are developing here, but all of them are intravesical therapies. We're the only company actually pursuing an oral. A targeted FGFR3 selective inhibitor makes a ton of sense here, given that this is the driving mutation that causes the majority of this disease. That's in a phase two study. That's advancing. At the same time, there's a really compelling opportunity in growth disorders. Achondroplasia or dwarfism is actually a condition that is caused by an alteration in the FGFR3 gene. Outside of somatic mutations in cancer, germline alterations in FGFR3, its primary role physiologically is actually a regulator of bone growth. It's actually a negative regulator. It puts a brake on chondrogenesis.
When you have an FGFR3 alteration that causes overexpression, it leads to that phenotype of short stature, disproportionate short stature that you see in dwarfism. With a simple once-a-day oral agent that inhibits FGFR3, we have an opportunity to potentially restore bone growth to a more typical paradigm. We're now actually treating children in a phase two as well with achondroplasia or dwarfism. Both of these studies in bladder and in dwarfism, we're looking to identify the right dose. It's a different dose that we're going to be seeking in terms of target engagement for these indications. We're very optimistic that with the data we've already generated with this compound, that we'll be successful. As a side note on that, we did report our first phase one data with this agent.
It was actually a phase one study in late-line metastatic, where we were able to demonstrate really high efficacy for FGFR3 positive MUC, over 50% ORR, and a really exceptional safety profile, highlighting that we had indeed spared the FGFR1 and 2 activity to reduce the toxicity associated with pan-FGFR inhibitors.
Wonderful. Bladder cancer and ACH are very different indications. Can you give us a sense of how you're balancing these two parallel opportunities in these FGFR3-driven diseases that are quite different?
Yeah, so I think at our heart, Tyra Biosciences is a company of scientists that are very, very passionate about the science. We made this drug. Initially, we anticipated we'd be able to move it forward in bladder cancer. What occurred was that when we passed all of the key safety marks, all of the preclinical testing that showed this would be safe for kids, plus got our clinical data in that late-line patient population, we realized this is also a drug that could work very, very well for growth disorders. It's a little bit of an embarrassment of riches, but our view is both of these conditions, given the unmet need, demand really an FGFR3 selective oral drug to move forward. Both are exceptional opportunities in terms of what the unmet need we could address and exceptional commercial opportunities.
We are moving them both in parallel forward and investing pretty equal resources in both. We built teams to be able to execute on these phase two studies very separate, even though it is the same agent, and are pushing that forward in parallel.
Great. OK, let's jump into NMIBC, and then we'll move to ACH afterwards. You've said that 70% CR at three months could be an attractive efficacy mark for urologists. What is that durability threshold? Could it be 12 or 24 months of recurrence-free survival, for instance, that would be convincing to you all, but also to the FDA to go to a registrational study?
Yeah, you know, we think about landmark CR out at 12 and 24 months as being important. Standard of care today, it's apparent that somewhere around 60% to 70% of patients, well, I should say 30% to 40% of patients are going to recur in that 12 to 24-month period of time. Being able to improve upon that, but even being able to meet that, but take away the need for general anesthesia, surgical interventions, and intravesical therapies is actually a really compelling outcome for patients. Being able to take all of these interventions and move it to an oral therapy, even at similar CR rates and maintenance, would be very important. That's what we hear from KOLs. You know, these patients, the 700,000 people in the U.S. with bladder cancer, there's a lot of them out there. Success would be giving them options.
Even if there are intravesical options that are tried, having an oral option, we anticipate most physicians, and especially patients, are going to be very happy to have this option to potentially tame their disease and avoid the surgical and intravesical interventions that they would need to otherwise have.
Makes a lot of sense. OK. You're studying two different doses, the 50 and the 60 milligram. What could the value to patients, physicians, and payers be if you see comparable efficacy? Would it be the incremental efficacy signal or a pristine tolerability profile in these patients?
You know, this is really about an acceptable level of efficacy with as much safety and tolerability as you can achieve. When we talk to investigators or KOLs about this, they've looked at our data that we've generated in a metastatic setting, which shows this is highly effective. We can push the dose to push high efficacy. It's really clear that bringing the dose down to the most tolerable level while maintaining this, call it 70% CR rate or better, is better than pushing the dose to try and get to a 90% CR rate and adding additional tolerability or safety issues that might need to be addressed. That's really what we heard. That was the real motivation for us choosing the 50 and the 60 milligrams initially for dose, because we did treat 10 patients in that metastatic setting at 60 milligrams.
What we saw was a very pristine safety profile and a profile that KOLs tell us, if that's reproduced in NMIBC and that's seen with efficacy, would be a very compelling TPP.
OK, great. TAR210 is intravesical or definitive. Can you talk about, you know, we've seen 90% CR rates, but it has a device-related burden. Can you talk about that a little bit and the differentiation of Dabagrotnib competing at that 70% benchmark versus the 90% CR that they've shown?
Yeah, I think the way to, again, it's really great for all of these options to be available. Moving beyond surgery is going to be very valuable. We certainly applaud the effort Johnson & Johnson is doing with TAR210 and others are doing in this space. I think these are going to be great options. I think the way to think about this is to put yourself in the mind of the patient first and foremost, and then also put yourself in the mind of the urologist as well. If you get an initial diagnosis of intermediate risk non-muscle invasive bladder cancer, it's likely going to be FGFR3 positive. You can confirm that pretty readily with even just a urine test.
It's really the difference between a physician saying, hey, I'm going to write you a script, and you're going to go home and just, you're just going to take this pill once a day, versus, all right, we're going to install this, we're going to install this device, or we're going to schedule you for surgery, and we're going to install chemo, and we're going to have you come back every three months, and we're going to take that device out and reinstall it. Even with TAR210, you're likely going to get some oral antibiotic at dose. You're going to get some systemic exposure as part of this. You're going to feel that device kind of sloshing around in your bladder. There are just certain elements of this that are going to be a little bit more burdensome.
Being able to go home with just an oral drug once a day, it's a pretty obvious point. I often like to use the analogy. I ask people, do you recall the drug Cabergectin? A lot of people don't. They do recall the drug Viagra. There was an injectable ED drug that was first to market that everyone was really excited about before there was an oral. It's just an obvious choice for patients. If there's an oral that's effective, you're going to want to try that. If 7 out of 10 patients are getting a CR and then maintaining that, that means when a patient comes back in three months and maybe they're the 3 out of 10 that didn't get the CR, there's other options. Why not try it? Because those 7 can then just stay on drug and control their disease for a prolonged period of time.
That's really the vision of what we think we can achieve and what investigators, KOLs are hoping we can achieve, and ultimately for the benefit of patients is that oral is an option. If it works, you can just stay on the drug, tolerate it well for a very long period of time.
The downside of that, it's like, you know, why not try an oral first? If you're not one of those 70%, you're back at square one, really. You're not any worse because the disease setting NMIBC versus a metastatic disease.
Absolutely. It's going to be great to have TAR210 or Johnson & Johnson's drug. It's going to be great to have these options as an alternative to surgery. I think the whole field's going to move forward in a very positive direction that way.
OK, great. Beyond oral, can you talk about the other differentiating features that might drive patients and physicians to want to use this drug? Would it be something like a UroGPO fitting into the mix? You know, what kind of dynamics help guide who gets Dabagrotnib?
Yeah, you know, a lot of investors wonder, you know, what's the incentive system for these urologists? They're very used to procedures. If you talk to a urologist, especially if they haven't heard about Dabagrotnib, which many haven't, because we're just moving into phase two, some of the KOLs are starting to perk up and pay attention. The average urologist is going to say, look, we do surgeries, we do intravesical therapies, it's easy, and they're able to do buy and bill, which you get 4.5% on the procedural drug spend back to your office. There's some money driven by that. What investors I think don't always appreciate is that there's been a very robust effort over the last 15 years with the oral prostate cancer drugs to help improve the incentives for those to be administered by the urologist.
The way that that's happened is that there's a group called UroGPO that's partnered with nearly all of the community practices and helped them establish a specialty pharmacy. That allows urologists to prescribe an oral drug and actually participate in the economics like they would with buy and bill, but they actually don't have to buy and then seek reimbursement. It's essentially a spread that they get that's managed entirely by the specialty pharmacy. They have the pharmacy license, they prescribe the drug, Cardinal Health, UroGPO does all the dropship, all the processing, guarantees reimbursement, and essentially sends them a check that makes it no less financially worse off to do that versus a buy and bill. In fact, it actually ends up being more convenient because they don't have to lay out massive amounts of money and then hope they get reimbursed.
Some of the urologists with some of the more recently approved drugs are talking about having to withhold partners' checks while they wait for kind of a million-dollar outlay to come back. That's not going to be the case with an oral drug. With these specialty pharmacies set up, there's no financial outlay, but they still participate in the economics for prescribing the drug.
Great. OK, let's move to ACH with our remaining time. BioMarin suggested that BMN 333 there could capture residual growth beyond Voxzogo's 6 cm per year AHV, which would potentially close the gap towards typical growth velocity. Could you talk about, you know, if they were to make some incremental headway past that 6 cm mark, how does Dabagrotnib differentiate and compete?
Yeah, I mean, I think first off, it's great that BioMarin is recognizing that there's a gap, right? That while CMP is a great step forward, and I think it's a great option, it's not getting to where the families and patients want. You know, now you have Ascendus that's generating similar data and, you know, removing the need for a potential once-a-day injectable, moving that to once a week, which is great for patients. Then you've got BridgeBio with an oral. Again, all of them aren't getting to that same 6 cm per year, which is not getting to where, you know, the community really wants to see growth. It's not restoring it to typical. Typical is going to be closer to 7.6, even 8 cm.
There's certainly an interest in a little bit of catch-up growth as well, because most people are starting on these drugs later and already have a pretty significant gap. It's great that BioMarin is recognizing that there's more efficacy on the table to be had. I don't know what the scientific rationale is, because we've now done multiple experiments with CMP, and you can increase the dose. It doesn't change the outcome. 6 cm is about what's achieved. Scientifically, that makes sense, because CMP is working on a pathway of accelerating growth downstream of the FGFR3 break, which is actually stunting growth. Even BioMarin showed that in kids that don't have this FGFR3 break, CMP does an amazing job getting them to 8.5 cm per year. This would be in Noonan syndrome or ISS.
With that FGFR3 break, if you're not taking it off with an FGFR3 inhibitor, there's really no scientific rationale to think that you're going to move beyond what these CMP agents have done. That is really the promise of an FGFR3 inhibitor. With a pan-FGFR inhibitor like BridgeBio, you can't achieve that promise because you're limited in your ability to move the dose up beyond where they've moved. They've had to go to a dose that's 1/6 of full target engagement of FGFR3, because when they're fully engaging FGFR3, they're also engaging FGFR1 and 2, and they're getting hyperphosphatemia and other tox. By moving it down to a significantly lower dose at 1/6 of full target engagement, yes, they avoid hyperphosphatemia and some of the other FGFR2 tox, but you're obviously not engaging FGFR3 in the way that you would like.
They're only getting to 6 cm, whereas if you were able to have an FGFR3 selective where we have a therapeutic index that we've shown in that late-line setting, you know, we should be able to push that well to getting kids back to typical and potentially even to what we think is a reasonable 8.5 cm target. It's not just belief. There's actually very, you know, very clear data of how this happens. That data has been generated with pan-FGFR inhibitors in children who have pediatric glioblastomas that are FGFR driven. In that instance, MSKCC published this report about a year and a half ago. When you use that full oncology dose while the growth plates are open, you know, kids are going to go from their typical 7.6 cm per year to 19 cm per year.
To put that in context, that's an extra 5 inches on top of typical growth. If your child's, you know, 5'5" and you expect them maybe to get to 5'6", instead, they're going to be 6'1" after a year. That level of growth is so fast that you actually start to see fractures, you know, and bone integrity issues. That's not where we want to go. That's where full target engagement takes you.
We're able to back down from there, from the data that we have preclinically and clinically, and lay out a very clear rationale for the doses we're testing in our phase two to say, these are doses that are going to push target engagement beyond what BridgeBio has been able to do with a pan-FGFR inhibitor into areas where we feel confident we can get to the right, you know, ideal amount of growth and pick a dose and then move that forward fairly quickly into phase three. That's really the goal of our phase two program.
Great. On the selectivity safety edge that you all have with the FGFR3 selective approach, what are the key pediatric safety events that you believe FGFR3 is mitigating versus the pan-FGFRs? What are the ones to watch in the pediatric population that you think are the most meaningful?
Yeah, I think, you know, people obviously talk a lot about hyperphosphatemia. That's an FGFR1-driven condition. That comes on, you know, pretty early. For example, with BridgeBio's data, they know that as soon as they hit 0.3 mg per kg, they're going to see phosphate levels rise. They saw that in their phase one. They have chosen a dose of 0.25 mg per kg. As I mentioned, that's about 1/6 of the dose that gets to full target engagement. The reason to avoid hyperphosphatemia is that unmitigated elevated phosphate levels can lead to tissue calcification. Obviously, for a chronic drug, you want to stay clear of pushing phosphate levels up to potentially dangerous zones. That's one.
Even with FGFR2, we don't talk about it, but when you look at the pan-FGFR inhibitors, the full target engagement doses, when you're hitting FGFR3 and 2 equally, FGFR2 is the key tox that leads to dose reductions in a drug like erdafitinib. 70% of patients are having their nails peel off in a very, very painful experience, and that's leading to 1 in 4 patients to dose reduce. 60% of patients are having their mouth dry up and get these horrible mouth sores, stomatitis. That's leading to 1 in 5 patients to dose reduce. Then you've got this PPE rash, which is this blistering and soreness in the hands and the feet. You've got eye tox. These are all FGFR2-driven conditions. You obviously need to spare FGFR2 as well. You don't want to be pushing it to these areas.
It's not going to be comfortable for children to be on a drug that's hitting FGFR2 chronically. It's important. It's really important to spare 1, 2, and 4, which we do with Dabagrotnib. It is the first drug to come to the clinic that truly has a meaningful separation from 1, 2, and 4, more than an order of magnitude. Even others that are attempting to come behind us, Abcuro, for example, has a drug in China, but it's an FGFR2 and 3 inhibitor. It spares 1. That's going to be challenging for them. Loxo Oncology at Lilly has an FGFR3 selective. It's a very good selective drug, but they have some ADME issues with that drug that appear to make it not feasible for moving outside of the metastatic setting. They are staying and investing there. They don't appear to be going into achondroplasia or NMIBC.
Getting to an FGFR3 selected drug with all the ADME properties is just a very challenging problem, which is, you know, we've achieved it with Dabagrotnib. We obviously have several years ahead of competition. I'm sure folks will ultimately bring out their small molecules, but it gives us a window of time here to really demonstrate leadership, optimize dose, get to the market with this drug, and hopefully address some really important unmet needs.
Great. Finally, when we look out 12 to 18 months for Tyra Biosciences, what do you think are the most underappreciated aspects of the story that could drive value? Maybe just give a preview of that time ahead.
Yeah, I think the most underappreciated aspect of our story is actually just the size of the unmet need and the opportunities that we have with this single drug. I think the data is out there. The clinical data is out there. The non-clinical data is out there. Johnson & Johnson's generated data in NMIBC. BridgeBio's generated data in ACH. This is a proven and validated mechanism. There should be a dose that we can achieve both on the bladder cancer side for NMIBC and ACH, and I think optimizes the safety efficacy outcome and allows us to move forward. I think what's underappreciated is just how much demand there is and how big a market both the oncology side and the achondroplasia side. For example, Johnson & Johnson just had their TAR200 approved yesterday. I think analysts are giving it an $800 million consensus peak.
Their internal forecast, Johnson & Johnson's, is $2.4 billion. They estimate that the NMIBC market for them is going to be a $5 billion plus opportunity with this pretzel, the biggest of which is going to be the TAR210, which is the FGFR inhibitor inside of the pretzel. That speaks to just unmet need, patient volume. Similarly, BioMarin's talking about what they're going to do with BMN 333 beyond achondroplasia, hypochondroplasia, Schatzki's mutations, idiopathic short stature, and also highlighting a $5 to $10 billion total addressable market across all these growth conditions. An FGFR3 oral selective agent has the potential to be a best-in-class for both of these and their very large markets.
We certainly agree. Thank you so much, Todd. Really appreciate your time. Thank you to the Tyra team. Thank you to the investors that joined us today in the room.
Yeah, thank you.