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We're good? All right. All right, good afternoon. Excuse me. Good afternoon, everyone. My name's Corey Kasimov. I'm one of the senior biotech analysts here at Evercore, and it's my pleasure to host our next discussion with BridgeBio. Thrilled to have you guys here. It's been our top pick for 2025, so thanks for coming through for us. Most of you probably know Chinmay, but we're also very—who's SVP of Strategic Finance in IR. We're also very excited to have Justin To, the CEO of QED Therapeutics, which is BridgeBio's skeletal dysplasia subsidiary. So, great timing, giving the pending phase three readout of infegratinib in the first quarter of 2026. So, thank you guys both very much for being here today. You know, to kick things off, and I'll say we have an extended conversation with you, so that's good too.
To start things off, it's a little bit of a loaded question with some very obvious answers. We're asking this of everybody. It's kind of when 2025 comes to an end and you look back on the year, you know, what would you say were the company's main accomplishments? I guess this is a good opportunity for you to briefly recap what has been a very eventful and transformative year.
Yeah, happy to talk about that. Maybe I want to first start by saying thank you, Corey, to you, as well as the entire Evercore team, Brad, Hank, and everyone else. We really appreciate you inviting us and hosting us. And lastly, and obviously, huge thanks to the investment community for supporting us throughout the year and joining us on our journey to help patients with rare diseases. So, 2025 has been a transformational year for BridgeBio. I would probably start by saying that the most important accomplishment this year has been a phenomenal launch of Attruby. We were very confident that we would be able to launch Attruby very successfully, get it to a lot of ATTR-CM patients. We knew that it was a large market. We knew that we have a differentiated label.
We know that we have, we consider it to be the best product for treatment-naive patients in ATTRCM. Having said that, the execution by our commercial team has been phenomenal this year, and I think that we ended last quarter at a run rate of about $440 million in revenue. Beyond that, we've also read out two positive phase three data sets, and I just wanted to take a moment to talk about these data sets because it is rare in our industry to find data sets which are curative, so most of the time, as all of you know, when we are looking to make a drug, we are just trying to slow the progression of the disease. Once in a while, you get an amazing drug like Attruby, which fully stabilizes the disease.
However, with both Encaleret as well as BBP-418, what we've been able to show is that not only did we stabilize the disease, we actually have started to cure the disease. In Encaleret, we cured it in about three-fourths of the population. And then with BBP-418, that's the first molecule which is shown in muscular dystrophies and improvement in function compared to a placebo which was declining. So, it's been a very eventful year. We're very excited about all the progress, and so that's where we are. That sets us up very nicely for 2026 also. And maybe what I'll say is, I think about the company in terms of just two numbers. We're going to make it simple for folks. I know there are lots of conferences going on.
So, the two numbers that I would want you guys to remember are one is $6 billion, and the second is $10 billion. So, what are these two numbers? $6 billion is what we consider is the fully de-risked peak sales potential in our pipeline today. That's $4 billion for Attruby and $1 billion each for both Encaleret and BBP-418. That gets you to $6 billion. The second is the $10 billion number, which is the peak sales potential of this pipeline. And in the remaining $4 billion, I account for infegratinib, which we are going to turn over next year in achondroplasia. That's a couple billion-dollar opportunity at least.
And beyond that, we're going to start a phase three trial in chronic HP, which is another huge opportunity we're going to use Encaleret to go from the genetic form of hypoparathyroidism, ADH1, to the broader population. And then we obviously also have programs in hypochondroplasia, which we're going to read out its phase two data set probably by the end of the year, as well as working on Fukuyama disease and LGMD2M and LGMD2U. So, it's a very exciting time for the company. We have de-risked $6 billion of peak sales, and I think that next year we're going to make good progress in terms of further de-risking towards that $10 billion number. And of course, that's the opportunity if you look at our market cap today for investors.
Love it. Six and 10, I like that. All right, so just to level set where we'll go here, we'll start with Attruby, and we'll quickly touch on your recent phase three wins. And then Justin, be patient. We'll get to plenty of questions to go on infegratinib. So, you know, starting with Attruby, you know, focus more on the big picture long-term potential of the product. And you kind of just touched on this. When you think about the ultimate sales potential here, you know, in the context of the view that the ATTR-CM market could be at least $15-20 billion overall, are you surprised that consensus peak sales expectations are still like below $3 billion?
Yeah, I think that we have said publicly that we believe that Attruby is going to be at least a $4 billion product. So, you know, there's no doubt that this is a $15-$20 billion market. The market continues to grow, and I'm happy to spend more time talking about it. Beyond that, I think it's very clear we today have north of 20% share in the treatment naive setting, which is the most important setting. We also get a lot of switch patients, which is great. So, if you just look at what we have today and you look at the size of the market, which I don't think is disputed by many on Wall Street, if anything, people think it could be higher. You do the simple math and you get to the $4 billion plus numbers.
You know, I think that that is an area of opportunity for investors as we continue to execute on Attruby and we go from $108 million in quarterly revenue to a higher number. I think that people get more cognizant of the opportunity, and hopefully that's going to reflect in the stock price. I don't know if I have any views on consensus, but it will be reflected in the stock price.
Okay. And now there are obviously a fair number of investors out there that worry about the future entrance of Tafamidis generics. To that end, you're generating a pretty broad set of data to position Attruby as the stabilizer of choice. Can you kind of walk through the key data sets that support that view at this point?
Yeah, that's a great question, Corey. And I think that I want to first start by looking at our label. So, that's data which is on our label today, and you guys can go read it up. It's on the FDA website. So, we are, number one, the only near-complete stabilizer. This is extremely important. You don't see the near-complete verbiage on any of our competitors, whether it's silencers or stabilizers. So, that's the first thing because this is a disease of toxic monomers. So, near-complete stabilizing the toxic monomer means a near-complete stabilization of the disease, which is obviously what we are looking for. The second thing which I'll talk about is the time to separation in terms of hard outcomes or the time to onset of effect.
We have shown on our label that our outcomes separate as early as three months, and we've done further work, and we presented this at HFSA to show that actually they separate as early as one month. That again is a very important data point because these are older patients, they're very sick, and they want to feel better quickly. Everyone wants to, you know, that helps with the long-term stability on the therapy too because if you're feeling better, you're more likely to stay on the therapy than, you know, if it takes months for you to see an effect and feel better. The third thing is obviously hospitalization and mortality, where we have the best point estimates at 30 months, right?
At 30 months, and I think it's important to look at the right time point, at 30 months we have a 50% reduction in cardiovascular hospitalization, which is extremely important for payers, and a 42% reduction in mortality and hospitalization. Now, beyond that, we've continued to generate a lot of clinical evidence. This year, for example, we have shown that if you add Attruby on top of Tafamidis, you get a sharp increase in the serum TTR levels. Meanwhile, if you add Tafamidis on top of Attruby, you don't see that effect. I'm sure some of you are wondering, why is he talking about serum TTR levels? We've also shown this year in the manuscript that increases in serum TTR levels are shown to actually be related to decreases in all-cause mortality.
And in fact, the increase that we saw on Attruby is predicted to have about a 15% reduction in all-cause mortality versus Tafamidis. So, this is the kind of data that physicians are looking for. They're looking to see what happens if they had a patient and they switched them onto Attruby, what kind of benefits you should expect. And the ultimate benefit is reduction in mortality because that's the most important thing in many ways. So, that's one data set which we've already published. Now, beyond that, we have shown in various subpopulations, such as the variant subpopulation, where we have the best point estimate that those are the sickest patients. And that's also a patient population which is severely underdiagnosed today. So, I think that there's going to be a lot of growth there.
The second important subpopulation where we have shown an effect, a strong effect, a very strong effect, is the AFib population, so recall about half of these patients, half of the ATTR-CM patients have some component of AFib, and we have shown the best point estimates in terms of reduction in AFib-related events compared to all other therapies, and it's important to note that some of the knockdowns actually go in the reverse direction in terms of AFib. We don't know why that happens, but that is what's been shown in the data set, so I think that we have continued to generate evidence. We are a science-first company. It's one of our core values, and I think you can expect us to continue to do that more in the next year, so we're very excited about switching studies and looking at biomarkers like NT-proBNP.
We're very excited about imaging studies. We are huge fans of real-world evidence. And so, we are very excited to have Attruby be out there in the real world and for physicians to now ultimately compare what happened to their Attruby patients versus their Tafamidis patients. And I think that as the cacophony of data continues, I think that we are going to be able to convince more and more physicians that Attruby is a differentiated product. It's not just another stabilizer. It's a unique product. It offers unique potential. And as you have seen in every other commercial class, even if a first-to-market less potent molecule goes generic, the second-to-market more potent molecule continues to grow. Nothing happens to its sales because ultimately this is a deadly, devastating disease, and physicians want their patients to be on the most potent molecule.
It's kind of how we're thinking about it.
Okay. What's the current desire to run a head-to-head study against Tafamidis that's focused on some sort of biomarker, NT-proBNP or something like that?
Yeah, I think we are considering it, but I think at the same time we want to generate evidence which is going to result in increases in share. So, we are obviously scientifically very curious about all kinds of things, but I think scientifically we are very convinced, just given the work we have seen in the serum TTR and the connection between serum TTR and mortality and hospitalization, that, you know, it's a superior product. So, for us, it's focused on what do we think physicians are looking for. And I think so far what we have seen is they're more excited about real-world evidence and some of these switching studies and imaging studies that we are doing as opposed to a true head-to-head study.
Okay. All right. In the interest of time, let's move on to Encaleret for ADH1. You've talked about this being a billion-dollar-plus market opportunity. What are some of the key assumptions that go into that when you think about the size of this market?
Yeah, so a few assumptions go into that, right? So, obviously simplest level, you have the number of patients who are treated, and then you have the price. In terms of the number of patients who you could treat, recall that there are about 12,000 patients who are carriers in the U.S. and about 25,000 in the U.S. and Europe put together. So, that's the size of the opportunity. Now, if you look at the serviceable opportunity today, you know, you don't think about any increases in diagnosis, which has happened with every single genetic disease out there. But let's say you feel like this is unique in some way. We have identified about 3,500 patients in the U.S. today, and we have about another 1,500 that we suspect have ADH1 just based on their EMR data.
That is the 3-5,000 opportunity today in the patient population just in the U.S., right? You have a similar sort of phenomenon happening in Europe also because, you know, our trials are all global. If you think about that and you think about any kind of rare disease pricing, right, I think that on the low end, what we tell people is you can look at things like CRISPR, which is about $400,000 or so, which is a similar price. And you can look at some of the more rare genetic diseases like the exon-skipping drugs as well as Prader-Willi and things like that. And those drugs can be north of $750,000. Even if you take the conservative end of that price point, you can easily get to a $1 billion opportunity just in the U.S., and then you have Europe on top of that.
Now, what's very important about this is that Encaleret works in all ADH1 patients, and this is another amazing thing, and you can probably hear the excitement in my voice, and some of you know me well, and I usually don't get excited about data like this, but it's remarkable that we went from a phase 2 study where we had a 70% point estimate in terms of resolution of the disease. We're talking about full resolution of the disease with normalization of blood and urine calcium, and in our phase 3, we went out, we had significantly more clinical trial sites, significantly more variants of the calcium sensing receptor, and we were able to improve our point estimate. To me, that's extremely rare, and you don't normally see point estimates improving in the phase 3 compared to the phase 2.
So, I think that, you know, this drug is very potent and it works on all these ADH1 patients. So, I think that that is how we think about the opportunity.
Okay, great. So, you know, when you take this the next step and you think about post-surgical hypoparathyroidism, how do you respond to investors who argue that calcium sensing receptor antagonism with Encaleret wouldn't work in PSH? Like what preclinical or clinical data support your view that it can in fact work in that setting?
Yeah, that's a great question, and I'm glad you're focusing on the broader chronic HP opportunity because, you know, it's a huge market and we're very excited about it. We're going to kick off a phase three trial next year. What I would tell those investors is very simple. You should go look up our phase two data set, which we published in September. We took patients who were the sickest of the chronic HP population. They had no PTH gland, right? So, we're talking about folks who could not produce PTH. We gave them Encaleret. Encaleret only works on the kidney, as I was describing earlier. We were able to show that 80% of the patients had normalization of both blood and urine calcium.
When we have done our market research and why we were so excited to take this in our phase three trial was we saw three axes of differentiation for this molecule. One was normalization of urine calcium, which is a huge unmet need in the HP community. We were able to do that at an 80% rate, same as the blood calcium normalization. The second is an oral option. And I think people underestimate commercially how important it is to just have the convenience of an oral option as opposed to an injection every day where you're going to have injection site reactions and all kinds of things. So, that was very exciting to us. And the third thing is just the safety, right? And so, there is a theoretical bone resorption risk with, you know, chronic PTH therapies.
We act completely orthogonally, so we don't have that kind of risk. And now we've even shown in the Encaleret phase 3 that the molecule was remarkably safe and well tolerated. So, I put all the clinical data together on the safety and the efficacy side, including the fact that we have shown efficacy in patients who have no PTH whatsoever. That gets me very excited about the phase 3 for chronic HP.
Great, great. Okay, so next up is BBP-418 for Limb-Girdle. And I guess, you know, why do you view the data that you had? Why do you view this as an unprecedented outcome in muscular dystrophies?
Yeah, that's a great question. And again, it gives me an opportunity to talk about the wonderful data that the team has generated. We're incredibly proud of it. So, let me just put the data in context for folks who don't fully know what we showed. So, Limb-Girdle muscular dystrophy is like all other muscular dystrophies, a disease where patients slowly lose function over time, right? So, they are slowly not able to walk properly. Their lungs don't work as well. And that's a slow deterioration, which eventually obviously leads to mortality. And we have a small molecule which works on alpha-dystroglycan. And we were able to show that by supplying a lot of the substrate in that pathway and increasing the flux through that pathway, we were able to actually start to show improvements.
So, for example, you know, not only did we show a static effect on the biomarker alpha-DG, both at three months and then that increased at 12 months. You always want to see things like that. So, very excited about the biomarker data that corresponded to a static drop in CK. Again, extremely excited about that. But what's been really phenomenal is just at 12 months, this is the first muscular dystrophy data set that I'm aware of where we saw a statistically significant effect on clinical endpoints, you know, functional endpoints. So, for example, 100-meter time test, right? So, we saw that patients on the placebo arm were declining in function and patients on the drug arm were actually improving in function. So, this gets to my point earlier that the disease was not stabilized. You actually saw an improvement in the patients.
We saw the same thing in FVC. And I think that we've not seen effects like this. So, that's gotten us very excited about this data.
Okay, so then how do you think about both the initial market opportunity for this program and then what's the plan to tackle other subsets of the kind of the broader Limb-Girdle indication?
So, the opportunity here, Corey, is about 7,000 patients in the U.S. and Europe. And again, if you look at the same kind of genetic disease price analogs that I was mentioning earlier, you can easily get to a billion-dollar-plus opportunity just with Limb-Girdle muscular dystrophy type 2I. Again, you know, similar to ADH1, we have a huge apparatus identifying these patients. And we have a lot of patients already identified, thousands we know already of. Beyond that, there's an opportunity to expand this population by about 50% just through, you know, expanding into LGMD2M, LGMD2U, Fukuyama disease. And so, we're doing a lot of work on that front. And I actually think it's also interesting to just note this tidbit that if you look at the pace of enrollment of the LGMD2I trial, that suggests actually a prevalence much higher than 7,000 globally.
We'll see once we're out there on the market. We don't want to be ahead of ourselves, but you know, maybe there's an opportunity to just increase the LGMD2I awareness and patient population. Beyond that, there's probably a 50% increase by these expansion indications.
Okay, great. All right. So, Justin, finally, thank you for patiently waiting. Finally, time to dig in on infegratinib and the opportunities in skeletal dysplasia. So, I guess maybe let's just start with the basics. And if you can just briefly walk through infegratinib's mechanism and how it differs from the current standard of care, maybe the key pros and cons versus the other approaches.
Yeah, happy to. Again, thanks for having us here. So, infegratinib is the first oral therapeutic option for the treatment of achondroplasia. And more importantly, it's the first targeted treatment for achondroplasia. So, for those who are less aware of achondroplasia, you know, it's a disease caused by gain-of-function mutations in FGFR3. And so, infegratinib is an FGFR3 inhibitor. Other drugs like the CMPs from BioMarin and Ascendis only target the MAPK portion that's downstream of FGFR3. But in achondroplasia, not only is there overactivation of the MAPK pathway, but there's also overactivation of the STAT1 pathway as well. And so, you know, because of that, infegratinib is the only therapeutic option that can target both pathways, which we will think it's pretty essential to really have impact on achondroplasia itself.
And so, in our phase two data, we saw best-in-class improvements in change from baseline height Z-score, you know, change of plus 2.51 at month 12 and plus 2.5 at month 18. Not only that, but we were really the first trial to show any type of statistically significant improvement in proportionality, something that the patients and caregivers really care a lot about. Proportionality basically is kind of how high your torso is compared to your lower limbs. And kids with achondroplasia have significant disproportionality as well. So, we think that between kind of the mechanism, the preclinical data where we showed significantly more bone growth and our phase two data set, that this could be, you know, just from the efficacy perspective, a very compelling treatment for families.
But more importantly, I think, or just as importantly, I think the fact that this is the first oral treatment is something that should not be overlooked because it's something that comes up time and time again when talking to caregivers and families.
Right, okay. All right, so as we dive in a little bit here, I want to start on the safety front because I think it's where we get most of the questions going into the phase 3 readout that's anticipated in the first quarter. There's some concern out there on the risk of hyperphosphatemia. Can you frame the safety profile in the context of what's been seen to date?
Yeah, let me kind of frame, again, let me just talk about what's been seen in the phase two, but then also then take a step back and talk about why, you know, we're not really concerned about hyperphosphatemia. So, in our phase two trial of about 72 kids, there was only one case of mild transient hyperphosphatemia, notably not even at the clinical dose we decided to go forward with for phase three. You know, so our cohort five, which was the main data set that showed the results I talked about earlier, had no cases of hyperphosphatemia. There was one transient case just barely above upper limit normal in a lower dose cohort. Now, taking a step back though, when we talk to clinicians and talk to KOLs, they're really not worried about hyperphosphatemia because what is hyperphosphatemia? It's transient increases in phosphate levels.
We know that other growth-promoting agents such as growth hormone, whether it be daily or weekly, in their labels, they have rates north of 20%, sometimes 30%-40% of hyperphosphatemia. They don't require any type of monitoring requirements. Pediatric endocrinologists are really familiar and comfortable with transient elevations in phosphate. For us, you know, we think that for our phase 3, honestly, anywhere south of 20% would be quite manageable and favorably looked at from clinicians.
Okay, so you anticipated my next question, which is like two-part and how confident you are that you won't see a high rate and you sound very confident, and then kind of what incidence would you consider acceptable, so somewhere below 20%.
20% of low-grade hyperphosphatemia.
Okay, and I mean, even 20% though, would you expect to see a number like that when you didn't see any in?
Yeah, again, until we run the phase 3, we don't know, but we always want to think about, again, from the clinician's perspective, what matters for them and what can drive usage, and that's kind of a number that we've heard of like, hey, if it's south of that, we're not too worried about that, especially since we know that the daily and weekly growth hormones have rates north of that.
Yeah, okay. All right. And then you've already touched on this, but if you can go in a little bit more into it and the kind of characterization of infegratinib's efficacy to date in terms of the annualized growth velocity, proportionality, and other metrics that you'd be following?
Yeah, so the questions were about, you know, the primary endpoints and the secondaries that we were measuring or kind of the data that we saw in the phase 2?
The kind of how the phase two you would think translates into phase three is really what I'm going to go with here.
Yeah, so again, the primary endpoint of phase three, it's going to be a 52-week trial, about 110 participants, two-to-one randomization between treatment and placebo. The primary endpoint for this is the same in our phase two, which is the change from baseline in annualized height velocity. You know, the secondary endpoints, there are two key ones that we're following closely. One is improvements in height Z-score, which I'll get back to that shortly. That's a very important one. And the second is improvements in proportionality. The main difference between our phase two and our phase three is that in our phase two trial, it's studied kids between the ages of five to 11. In our phase three, we're actually going after a broader population looking at kids three to 18.
This is slightly different from what BioMarin did and slightly different from what Ascendis did, which I know gives investors headaches because we can't do a proper cross-draw comparison. So, BioMarin did 5-18 for their initial trial and Ascendis did 2-11. So, we're actually kind of, this phase 3 will be the broadest population that has been studied in achondroplasia. And the reason for that is because we want the broadest possible label, especially given the strength of the data that we saw in our phase 2. The trade-off though is we know that kids who are younger, so like the ages 3-5 and kids who are older, so 11-18, we know from the other trials that there tends to be less of a treatment effect because those kids just don't grow as much.
We do expect a bit of a diminution of the treatment effect from the phase 2 to the phase 3 because of that. I think for us, anywhere north of like 1.5 centimeters per year will be great to see in our phase 3. But more importantly, or just as importantly, this is why I mentioned that one of our key secondaries is change in height Z-score. This change in height Z-score will probably be a great friend to investors because it's actually a really helpful way to compare across trials. What height Z-score is, is effectively it normalizes the change in height based on a participant's age and gender. It basically just looks at the population mean and kind of plots it compared to that.
So, BioMarin and Ascendis both saw an improvement in height Z-score on average of plus 0.3 from the achondroplasia population mean. So, I think as long as we can see that, I think that can kind of show you some comparability between the trials.
So, I guess can you follow up on the anticipated, like what you think would be a positive efficacy outcome? You said anything above 1.5?
Yeah, and the reason why, you know, you know, we didn't pick that number out of the hat, which I would love to say that, you know, we did a lot of market research, talked to clinicians and did a number of surveys and panels. And the number one thing that comes across from these discussions is the number one biggest driver of potential adoption for a new therapeutic is the ease of convenience, the ease or convenience for families of a route administration. That was the number one thing. They're like, if all else is equal, if efficacy is the same, in a three-way marketplace between BioMarin, you know, Ascendis and infegratinib, over 50%, sometimes 60% of clinicians would rather just pick the oral. And we think that number is even higher for families and caregivers, right?
Just because, you know, who wants to be injecting their kid, you know, every day? And so that's why we think 1.5 is the bogey for what's going to be a commercially successful launch.
Okay. Do you plan when you either topline this or when you provide more detailed data, a future medical meeting, will you provide data kind of stratified by age groups that would enable people to sort of compare your phase three data more apples to apples with your own phase two data?
Yeah, yeah, so you know, as our topline, I think it remains to be seen because again, we're going to have to release data pretty shortly after having it, so we're going to be prioritizing the topline, which is the population mean and the key secondaries for a topline. Probably for major medical conferences, we'll look more into kind of producing some of the subgroup analyses. Although again, the caution here is even though it's a 110-person trial, the subgroups are all probably going to be quite small to compare between the trials. This kind of goes back to my earlier point though, that one of the best ways to compare across trials will be looking at the height Z-score just because that kind of normalizes across three trials based on the different population mean, like ages and genders as well.
Okay. And when you go back to the phase two, I wanted to ask about kind of the trajectory of growth that you saw because you had cuts at month six, month 12, month 18, and you saw the obviously the big jump and then that attenuated a little bit and then was stable out to month 18. Kind of how would you explain that trajectory that you saw?
Yeah, so this kind of phenomenon of kind of like a spike at month six and a steady state from month 12 to 18 is pretty. It's not specific to infegratinib. It's something you kind of see across all achondroplasia trials. It's almost like a statistical kind of noise based on the way the endpoint is measured. The endpoint is annualized height velocity. You basically measure how much a kid grows and then you try to smooth it out across a year. When you look at, when you do it across six months and you annualize it, basically any noise that's captured in the first six months gets amplified by two. Typically you do want to look at month 12, month 18 to have the smoother height Z-score.
And so we're confident it's not some sort of like weird one-time signal, one-time noise or loss of effect because what you see from month 12 to month 18, importantly, is that the treatment effect effectively stays flat. You know, it was at plus 2.51 at month 12, plus 2.5 at month 18.
Okay. And then with competitor trials and Ascendis specifically with their long-acting CNP, I mean, they showed stronger outcomes in phase three than they did in phase two. Do you have any takeaways from that experience? I mean, you've broadened your age range for phase three, so you wouldn't see that dynamic at play. But anything from that that kind of informs how you think about infegratinib?
No, I think again, it's hard to kind of comment on the specifics of their trial. And I will say across all the different phase threes in this space, whether it be BioMarin, Ascendis, and ours, site selection is similar, right? We all kind of use the same centers of excellence, all use the same ways of measuring endpoints. So, it's kind of hard to kind of talk about what happened in their trial from going from phase two to phase three, but I don't kind of anticipate kind of one-off trends happening in one trial that aren't seen in other trials just because we're all using the same sites and centers of excellence.
Okay. And then, I mean, I guess to put it bluntly, like what do you see as the main risks going into phase 3? I mean, you sound very confident talking about it, but what are the risks there? What worries you?
Yeah, I mean, I think for us, you know, we talked about the efficacy signal, right? Again, and I think based on what we saw in the phase 2, we feel pretty good of being able to hit the bar of 1.5 centimeters per year for age 5. I think the biggest risk, and I don't really kind of see this as a risk, but there might be a misconception that just because we hit proportionality in our phase 2 at month 18, that we're going to for sure do it again in our phase 3 at month 12. And to be honest, it's going to be a little bit of a coin flip. You know, we don't necessarily know whether we're going to hit it or not just because no trial's ever seen an effect at month 18, let alone at month 12.
You know, I think if we're measuring this endpoint later on at month 18, month 24, I think there'd be a greater chance, but at month 12, I think it's going to be a little bit of a coin flip. If we were able to really hit at month 12, I think that would be a home run for us.
Okay.
Maybe I'll also just add, it's similar risk as all our other trials, right? If you think about it, we went from cohort five, which was tens of children, to now phase three, which is more than 100 children, and so you have more sites, just more heterogeneity, and as Justin mentioned, you know, one of our learnings has been you want the broadest possible label at launch, so we also broadened the age group, so there are multiple things here which should attenuate the signal, and so, you know, it remains to be seen if we can, you know, replicate strong data and get above 1.5 centimeters per year, but I think that until we do the experiment, we won't know. We feel good about doing the experiment, but we cannot predict the outcome of it.
Okay. I guess, well, there's a few questions, a few directions I want to take this. You know, so it sounds like you would expect if this trial goes as planned that your initial label would include ages three and up. Is that right? How difficult is it to dose a three-year-old with an oral formulation?
Yeah, I think it's a great question. So, I think there's this misconception that Infegratinib are like horse pills and you take several of these horse pills a day. So, it's a once-daily capsule and the capsule itself is quite small. This capsule inside has small mini tablets anywhere from three to five or seven or so. And these mini tablets are each the size of, sorry, one-third the size of a grain of rice. So, very easy to take. These mini tablets can be sprinkled on food, sprinkled directly in the child's mouth or the whole capsule could be taken intact as well. And from our discussions with kind of sites, it has never been an issue to administer, even to the youngest kids, actually.
Three-year-olds don't have trouble getting. I mean, I have two kids. I've seen when they were three years old, food ends up everywhere. So, if you try to put it in food, like, to be sure that you're getting the proper dose taken by the kids.
Yeah, no, it's definitely been a really good experience with the sites and the caregivers where, again, I think the families are very thoughtful about how they administer it to the kids. Every family situation is different, but we haven't really ever heard of issues of administering to young kids.
And then.
Actually, Corey, I'll just add, we've invested a lot in this formulation. So, this mini tablet concept that Justin's talking about, there's profound innovation there just in terms of making sure that, you know, a small child can also easily take the drug. So, I think we don't talk about it a lot because it's not sort of, you know, PhD science, but it's actually quite innovative as to what the team has done here.
Okay. And then BioMarin's Voxzogo goes approved from like the time of birth onward. And they talk about most of their use now is in those infant patients. Can infegratinib, can the formulation ever be updated or if it even needs to be updated to get down to newborns?
Yeah, so two things there. One is we will be eventually starting our trial in the youngest kids, looking at kind of infegratinib in kids from birth to two to three, so that we can ultimately update our label to include from birth, just like with Voxzogo as well, so that is going to be a key priority for us. To your point around the formulation, so, you know, the youngest kids, kids from birth to six months probably will need some different type of formulation, which is something we're actively looking at. But kids from six months and up would be able to take the current formulation.
Okay. And does your market research suggest if a child is on Voxzogo or eventually on Ascendis's TransCon product, once they've been on it and they're doing well on it, that they would still switch over to infegratinib because it's an oral pill?
Yeah, so we've done research in both the treated and naive, which I want to come back to in a little bit, and the kind of families who are currently on treatment today and trying to understand switch dynamics and adoption dynamics. We've heard resounding interest, even from families who have been on Voxzogo since the day it was launched, to switch to an oral formulation. I think there's really no degree of necessary stickiness just because, you know, just because if you've been injecting your kid every day for a few years now, you know, you don't necessarily get used to it per se. I think you still want to look for a better treatment option, especially as they kind of get older and you have to adapt with, you know, your daily routines as they grow up as well.
Okay. I guess, you know, to be just to be clear, is your view on infegratinib's like kind of value proposition, is it changing at all to be more in line efficacy-wise, but with the convenience factor of being oral? Or do you still anticipate that it's going to be the most efficacious of these products as well?
Yeah, I mean, ultimately I think it will have to depend on what the phase 3 will show, right? Because I think in my heart of hearts, and from talking to clinicians, they understand the scientific appeal of having something that is truly targeted, not only hitting the MAPK pathway, but the STAT1 pathway as well. You know, whether or not that gets borne out in a 12-month trial versus longer-term data on other important endpoints remains to be seen until we kind of see the phase 3 data. But I think at the end of the day, we will kind of be able to find some, see some data that shows that having a targeted therapy will have treatment effects over the long run that are better than that of the CMPs. That being said though, right?
Even if we don't kind of see that in a 12-month trial, I think the value proposition of having the daily oral is going to be a very key driver of adoption. There's two reasons for that. One, again, going back to what we hear from caregivers, the route of administration is the number one kind of importance factor for families looking to switch today who are currently on therapy. Second, I know, you know, a lot of noise has been made recently about Voxzogo's recent performance in the U.S. There's a sizable proportion of patients and families in the United States, I would say close to 60%-70% of the U.S. market that are not on treatment today. That's not because they don't want to be in treatment. In fact, most of these families are interested in treatment.
They're just kind of on the fence right now because Achondroplasia is not a lethal condition, and how do you win over a family that's on the fence about treatment, not with a daily injectable, right, and so these families, many of them are actively interested in treatment, but they want something better than a daily or a weekly injectable, and that's where we come in.
Okay. Something else we hear in our KOL conversations and we see advocacy groups talk about this as well is kind of this almost frustration with this overreliance on growth velocity for these kids. You know, you speak to proportionality and things like that that you'll get in your dataset. You know, these benefits beyond just height, do you expect this to be reflected in your label and how important is it that that is there at the end of the day?
Yeah, I think there's a few things about that. One is, you know, we will be continuing to study infegratinib beyond just the phase 3 52-week trial, right? Looking at other endpoints over time that we can hopefully see important improvements on, whether it be skeletal health, leg bowing, spinal health, quality of life, and I think that is going to be really important for families that who care about outcomes beyond height. You know, whether or not, you know, that ends up on the label, I think that will kind of depend on discussions with agency and what's within scope and out of scope, but I think we're going to be really thoughtful and aggressive about publishing to make sure all the available science and data is out there to support why we think infegratinib is the best agent out there.
Okay. And then assuming the phase 3 trial goes as you hope, and this is on the market, how do you see infegratinib kind of performing and competing as what would likely be the third entrant? Like, where do you expect the initial share to come from and how rapidly do you see that market evolving?
Yeah, I think the market will evolve quite rapidly. You know, from the families who are already on therapy today, we know, you know, just from our experience with clinical trial sites that there's a lot of pent-up interest from families who are on Voxzogo today to switch to daily oral once it's approved. It might not happen overnight, obviously, no launch, you know, has a rapid switch overnight, but we know the interest is there from our discussions, and I think just as importantly, I think infegratinib will be the first program that can unlock that treatment naive population today, which is a huge number of families in the United States.
Right. Okay. You know, BioMarin has talked about the fact that 75%-80% of global Voxzogo sales are outside of the US. How quickly can a company like Bridge ramp up the kind of the OUS capabilities?
Yeah, let me talk about that in two ways, and feel free to jump in later as well. I think BioMarin really focuses on the ex-U.S. side of things just because, you know, they don't really want to talk too much about how the U.S. market is underpenetrated. I think that's an area of significant growth for us when we come in, right? That population in the U.S., we're either needlephobic or, you know, aren't interested in daily injectable today for other reasons. I think that's going to be a clear growth area for us that's still quite intact. On the ex-U.S. side of things, I think we're going to be well prepared, not just for infegratinib, but for other franchises as well to launch and win a good share, right? Down share.
And the reason for that is, you know, these centers of excellence. It's not like Attruby where it's like disparate in like 40 different sites in a given country. There's only about three or four experts in any kind of given major market country. And we already know who they are. We work closely with many of them. Some of them are clinical trial sites today. So, I think we're going to be quite effective at being able to drive adoption in major ex-US markets as well.
Okay.
Maybe I'll just add that we've actually built an extremely strong ex-U.S. team. And remember that even for acoramidis, you know, if you look at all the ex-E.U. geographies, you know, whether it's Brazil, whether it's Canada, BridgeBio is the commercializing entity. So, we know that even for acoramidis, we had to build a big, you know, we had to have an international presence. And then with, you know, extremely strong datasets in ADH1 and Limb-Girdle, and obviously really excited for the infegratinib potential opportunity here, we've gone ahead and we've hired a few extraordinary individuals. Actually, the person used to be a senior Alexion executive, commercially, now heads our international office. Actually, Justin's being a bit coy. He just came from our international office. So, he's met all of them. And there's a lot of cross-country travel that's happening.
I think you guys know that we're not shy in terms of getting on the flight, seeing our people and making sure things are going okay.
Right. Okay. So, I was going to ask, because we've kind of rounded out this conversation, you know, you're going to be filing at least two, maybe three new applications. Each of these products has global ambitions. I was going to ask how difficult you think it's going to be for a company like BridgeBio to pull this off. Sounds like you can do it and you're already well on your way. I guess the next question that's tied to this and then the question we get frequently from investors is, do you have the balance sheet to pull this off, and what kind of levers can you pull to address the lingering investor concerns on this front?
Yeah, I'm happy to talk about that. So, we have about $650 million of cash on our balance sheet today. If you look at our spend, it's been roughly flat over the last three quarters. And if you look at our revenues, they've gone up. So, that makes it to be a very good financial situation where our burn keeps dropping. Our expectation at Bridge is that even with, you know, filing two and hopefully three applications, both nationally and internationally, and then commercializing potentially up to three products and running all the expansion indications, we don't really expect our cash burn to go up, just given the fact that Attruby continues to inflect the sales. And so, you know, you take that burn into account with the fact that we have a very strong balance sheet of $650 million of cash on hand.
If you look at our debt situation, you know, we have $1.8 billion of debt, but about $1.2 billion of that, or $1.1-$1.2 billion of that is converts, which are deeply in the money. We don't really have to worry about that in any way. I think we put all of that together and feel really, really good about where we are and the business which we can build, you know, based on the potential of our drugs here.
Awesome. Well, we're down to 15 seconds. I think we're on to there. It's going to be exciting to watch this all evolve. So, thank you guys very much for being with us here today.
Yeah, thank you, Corey. Thank you, Adi, and thank you, everybody.