On this, our second day of our 2024 Healthcare Conference in Las Vegas. For this section, I'm very pleased to host Neil Kumar, Chief Executive Officer of BridgeBio. Neil's going to walk us through some slides, and afterwards, we'll have some time for Q&A. I'll pull from the audience, but I have a few of my own in case everyone's shy. So with that, Neil, thanks so much for joining us.
Thanks so much for having me, Jason, and thanks to the whole JPM team for the opportunity to present here. I thought I'd take the first maybe 15 minutes or so, as Jason just mentioned, to sort of frame where we are as a company. And I know it's a little bit late in the conference and a little bit late in the day, so I'll issue the normal corporate overview and actually dive right into three key topics that we've been getting quite a few questions about from investors. First and foremost, is really how to contextualize upcoming clinical data, namely from the HELIOS-B trial, in and around the data that we presented for acoramidis and through our ATTRibute trial.
So I'll spend some time there, helping to contextualize at least how we see the playing field. Secondly, I'll give some updates on how we intend to communicate long-term follow-up data for our infigratinib program in the context of achondroplasia. And then finally, I want to touch a little bit on our own corporate strategy in today's marketplace, and how the spin of BridgeBio Oncology Therapeutics derives from it. I'll just remind everyone, that this is a highly dynamic time for the company, as everyone knows. First and foremost, our goal is the successful launch of acoramidis in the ATTR-CM marketplace. We also have three ongoing phase 3s that we believe are either best-in-class or first-in-class molecules in $ billion-plus dollar marketplaces, and then an ongoing phase 2 in congenital adrenal hyperplasia, coupled with an earlier stage pipeline that we continue to progress.
Within the context of ATTR cardiomyopathy, there's a lot of exciting data that we're publishing. We are in pre-promotion stage right now, so there's not much else we can do other than put the exciting data out associated with the ATTRibute clinical trial, as well as to kick off new trials like our ACT-EARLY, early prevention trial. As many of you know, we demonstrated 100% survival in an ongoing phase 3 with our partners at AZ and Alexion in Japan. We published excitingly just this past weekend at ESC Heart Failure, the ACM data or mortality, exciting relative risk reductions that we were able to achieve in our ITT population of 632 patients, which were inclusive of our sickest patients, and that offered a p-value of 0.04 for ACM alone.
We'll have a lot more to say about and a lot more abstracts coming up at ISA here at the end of May, which is perhaps the most important amyloid conference of the year. All of this is happening within a landscape of us diagnosing many more patients on an ongoing basis. As you saw, I said, probably easily from the tafamidis quarter-on-quarter growth or the 60%+ annualized growth. We're finding a lot more patients, and we're getting a lot more of those patients on drug over the over the course of time. So that's, I think, exciting, regardless of whose sponsor you're talking to or what therapeutic you're speaking about. We were also able to strengthen our capital base over the course of the last several months.
We've done it mostly away from equity, given our lagging share price, but we've done it in partnership with some of the strong royalty debt and now pharma partners on the commercial side that we're very privileged to be working with. And then we were able to unlock some early-stage value with BridgeBio Oncology's spin out, and I'll talk a little bit more about what shareholders can expect from that and other similar situations going forward. Okay, so let's spend a little bit of time on ATTR cardiomyopathy and just how we think about the ever-evolving landscape. And here, I should say just at the outset, we are rooting for and do believe that vutrisiran will come to the market. There is no one or even two therapies that will cure adequately for the entirety of a population like this.
Our belief is they have an effective and safe product that will come to the marketplace. Ultimately, our aim here is to clear up any misinformation. There have been many, many analyst notes, I think, written on this trial and what the bar should look like, and we just wanted to put forth what we believe the ATTRibute clinical data effectively suggests for how patients and physicians might view these products side by side. So if you remember anything from the presentation, this is really the key slide in terms of trying to understand what the bar is within ATTR-CM. Really three numbers. The first is 42 and 3, the second is trends favoring acoramidis, and the third is 30 months.
So maybe on 42 and 3 , as many sponsors have, us and Alnylam noted that there are many fewer deaths occurring in clinical trials today, thankfully, given the improvements in clinical care. And so the composite endpoint of all-cause mortality plus cardiovascular hospitalization is really how we think about relative risk reduction. And here, what we were able to show in the ATTRibute trial was a 42% relative risk reduction over the course of 30 months against that composite endpoint, and with those KM curves separating materially at three months and continuing to separate over that course of time. So 42% relative risk reduction and a three-month separation is really how we think about the monotherapy arm of the upcoming clinical data that will be presented.
Now, as many of you know, within the context of these ongoing clinical trials, what we're also able to do is to cross-compare within a single trial how we're doing against tafamidis. These trials are not designed to be double-blind head-to-heads. These are all post-hoc exploratory analyses that are not confirmatory in any way, shape, or form. But we obviously do get quite a few questions about how our drug versus tafamidis did in the context of the trial. We've published a bit of that data, certainly in the context of NT-proBNP ... and serum TTR, and I think it's important to note that from a point estimate standpoint, there's nowhere in our trial where we look, where acoramidis is not outperforming any other agent that was available to patients within our trial.
Again, with the caveats that very few patients were on tafamidis, and they were on for a shorter period of time than they were on acoramidis. So that's gonna be something that people will be looking for in the context of upcoming clinical trials. How did the population on the investigational agent compare to the population that was on tafamidis itself? And then finally, 30 months. As all of you know, these are not classic Cox proportional hazard-type curves. What you see is an ever-enlarging separation, certainly as it pertains to ACM and CVH. As the trial on goes, I think Pfizer had published some very interesting data suggesting that with every six months of elongation, you pick up another five to seven percentage points or so of relative risk reduction.
We're gonna need to go back and look at what things look like at 30 months, which I assume we will have, given the time series that all sponsors are likely to publish. So those are really the first three things, and I'll get into a little bit more data against each of these. In the context of number 1, what you can see here is, again, KM curves as they pertain to all-cause mortality and first cardiovascular-related hospitalization over the course of 30 months. We have published this data. Maybe a couple of things to point out. Obviously, the separation at three months is something we had not seen before.
The striking 42% relative risk reduction is also something that we haven't noted, or at least anything of that magnitude, as far as we're aware of in this space, and you can see the p-value of 0.0008, which is highly statistically significant in the context of our ATTRibute trial. I should also point out as it relates to the second point, that we mentioned in terms of, intratrial comparisons, we were able to look at NT-proBNP levels and serum TTR levels. And in both cases, what we were able to see was that acoramidis, given its higher levels of stabilization, was able to outperform, those patients, both on placebo or placebo plus tafamidis, in our clinical trial. This is data that we have already presented, on the left and on the right.
And then, as many of you know, and we'll be publishing on, and talking about at upcoming conferences, excitingly, within the OLE, we can take patients that are on other investigational agents such as tafamidis, and actually put them on acoramidis and see what that does to levels of serum TTR or in vivo measure, if you will, of stabilization. And here, what you can see on this slide are that the patients that were on tafamidis and ultimately received acoramidis, actually are able to avail of the higher serum TTR levels or the higher levels of stabilization that were not reached on a partial stabilizer.
So that, in concert with some of the data that we talked about earlier and we'll continue to publish on, which links ever higher levels of serum TTR to lower levels of mortality and hospitalization for the first time in the wild type population that had already been published on in the variant population, is a very, very exciting advance for patients. Finally, why is 30 months important? I should just remind everyone that at 30 months, we interrogated our endpoint on the basis of the FS test. That's a hierarchical analysis, very, very similar to what Pfizer used, which was also the FS test. But you can also look at another SAP, the Anderson-Gill, which does not hierarchize mortality and hospitalization. And what we were able to demonstrate, again, at 30 months, was statistical significance against that endpoint of ACM and hospitalization.
And as I mentioned at the outset, with every five months of... or six months, I'm sorry, of increased duration, you can see another, five to seven percentage points of relative risk reduction potentially being picked up, and there's a wide variety of ways one can model this. But we call those the alligator jaws, and they are ever-increasing, as you go out in duration. So that should increase the probability of technical success of any trial as you go out further in time. Okay, so, what does all that mean? Obviously, we're eagerly anticipating the data from the ongoing HELIOS-B trial. We're also eagerly anticipating, the largest amyloid conference of the year, which will be ISA, again, held in Rochester, Minnesota, this year, where we'll have more than 15 abstracts.
We had set the goal to publish at least 20 different pieces of research in subpopulations and otherwise in the first 18 months post-ATTRibute, and I think we're gonna handily beat that goal. So we are trying to excavate as much information as possible from that dataset, as well as contributing new data to the field through some of our ongoing phase IV and lifecycle management trials that are kicking off, most importantly, our ACT-EARLY trial. And so we'll continue to push on that, and we also eagerly await, obviously, approval toward the end of the year as we ramp up into having a commercial presence in the ATTR-CM community. Okay, so that's basically what I wanted to say on ATTR-CM. Happy to take any and all questions on that front after my comments.
Let me move then to Infigratinib and our achondroplasia program. At the outset of the year, we had talked about how we intended to share data as it related to PROPEL2. PROPEL2, as a reminder, is our ongoing phase II clinical trial with two preplanned cuts. One was at six months, and the other was at 18 months. Originally, our intent was to publish this data in a high-impact journal, if the data were positive, obviously, by the end of the year. We still intend to do that, but given feedback from KOLs and the community that we serve here, we would also like to top line the data, as soon as possible. As soon as possible is once we're done collecting data from 18 months, which we should be in early June.
And so, at that top line, PR, what we hope to accomplish with it is effectively three things. The first is the continued safety of our compound. Obviously, that's something we keep a close eye on, given the population that we're trying to serve here, and safety out at 12 and 18 months, I think is gonna be very important to see. We obviously saw a very benign profile at 6 months, and our hope is that it extends out further to 12 and 18 months. Secondly, we'd love to see continued evidence of best-in-class efficacy.
I'll talk a little bit more about quantitatively what that looks like, but certainly a change from baseline that's above what has already been established in the field at 12 months, which is a 1.35 cm per year change from baseline. And then finally, as many of you know, given the fact that we are targeting this disease at its source, very different than many of the other approaches in this space, and when one looks at what's possible when you both hit the MAPK effector pathway in concert with a JAK-STAT effector pathway, what we have at least seen in animal models for this condition is that one might provide, in addition to impact on AHV, impact on other things like spinal stenosis and proportionality. And proportionality is one of the first things that we can look at over the course of time.
So our hope would be that we could see something like a trend on proportionality. We've also met with regulators, and they've told us that if we're able to see things like that as a key secondary, there would be potential for us to include that in the label, which would be very important, we believe, for this community. So the hope there is trend. Obviously, the ends are low in these trials. If we were able to hit statistical significance, that would be a big home run for us, but at the very least, we'd love to see a trend there, similar to what we saw in animal models. I'll just remind everyone of what we saw at... In our six-month data set.
I think most of you in the room, as I can tell, are familiar with this data, but we were able to see a meaningful change from baseline in terms of AHV. That was married with a very, very high responder rate, a very, very high absolute magnitude of AHV for the patient population. And just recall that this is the right way to measure efficacy, which is effectively within an individual to establish their baseline and then ultimately to look at how they do on drug. Should also remind that these baselines are very similar to what's been studied in the past from some of our competing agents in terms of mean age as well as baseline.
In fact, we're probably handicapped a bit by the baseline because there's effectively an inverted parabola if you look at the phase 3 data from BioMarin in terms of where you see the greatest efficacy as a function of baseline. Then importantly, for a product like this that's targeting this well-described disease at its source at a low dose, we wanted to have a look at safety, and again, at six months, we saw a very, very benign profile. We'll just have to see how that plays out.
So just to reiterate a little bit on the different cases that we're looking at, you know, first and foremost, when we took on the assignment of trying to create a best-in-class therapy in this space, we had thought that an oral and safer agent, as compared to what was out there in terms of CNP or CNP analogs, would first and foremost be an important advance for patients. Obviously, an oral avoids things like injection site reactions and avoids things like hypertension associated with the CNP class. And so what we had hoped to do was to have a well-tolerated safety profile with a more convenient agent that could be sachet formulated and to meet or beat that 1.35 bar. That's obviously not our hope.
Our hope is that as we target this condition at its source, with the FGFR3 gain of function and affecting both the effector pathways versus just one and one minimally, our hope is that we can do something even better for patients, both in terms of safety and convenience, but also in terms of efficacy. That's certainly what we saw in the six-month data, and so our hope is that we continue to markedly outperform the benchmark that's been put forth, which is 1.35 cm per year over the course of 12 months. And then, as I said, aspirationally, our hope is that we start to see signs that this agent can do something beyond just growth velocity for the community that we're serving here. And those first signs we'll be looking for is in the area of proportionality.
Okay, so what are the next steps? Next steps here for the overall program are full enrollment of our ongoing PROPEL 3 study, which has been enrolling quite nicely. FPI for our hypochondroplasia study, which, as we mentioned at JPM, should occur well before the end of the year. And then ultimately, delivering on the full value of this program across a suite of FGFR-driven skeletal dysplasias. Could be FGFR2-driven, could be FGFR3-driven, but certainly, we're gonna be aggressive in taking it to wherever we might be able to serve patients with the best or first-in-class medicine. Okay, with a couple of minutes that I intend to talk more before I take questions, maybe I'll just briefly talk a bit about the strategy of BridgeBio and how then the BridgeBio Oncology Therapeutics spin derives from it.
I'll just remind some of you, there's a few of you in the room that have been involved with BridgeBio since we were a private company, but there's effectively only two equations that drive what we intend to do here as an organization. The first on the left is effectively to deliver as many drugs as possible to as many patients as possible in the shortest period of time. And so what that basically means is how many quality-adjusted life years can we deliver to the patient communities that we serve? If we can deliver three drugs and optimize that, then that's great. But if we can deliver four in the same period of time, that's even better.
We couple that by saying that every program that we take on needs to be NPV positive and that we're trying to maximize within the concert of that first equation, overall value to shareholders. The way to do that is obviously through a focus on ROIC, G, and WACC. These two things combine quite nicely. Obviously, as we take on more and more programs, our availability to drop our cost of capital through debt mechanisms and others, as you've seen us use, becomes more and more possible. So there's an interrelatedness that we've been able to take advantage of over time to serve more and more patients.
The issue for that has been that over time, the marketplace, and certainly with investors, we've been listening carefully to them, have wanted a more focused organization, especially given the fact that even the four programs in our phase 3 are hard to focus in on. People generally have a view that they're gonna focus in either on TTR or achondroplasia, and we certainly don't get as many questions even on ADH1 or LGMD2I, as we think those programs might warrant, given the fact they are both in phase 3, nearly completely enrolled and set to read out next year.
So the question is, with an engine like ours that we think very credibly has been able to create great progress in terms of research, certainly 17 INDs in under 8 years, I think, is one of the more productive biotechs I've seen or been a part of, a couple of approved products with a, with a third on the way, and generally being able to push ideas all the way to IND in less than $10 million. How do you take that capability and continue to do something special for investors when it generally looks to a lot of you in the room like burn rate that you're not being rewarded for? And so we, you know, we explored a lot of different ways that one might actually be able to do that.
For those of you in the room that, you know, were covering Genzyme back in the day, there is the availability of things like tracking stocks. We've looked at differentiated structures like an MLP structure, which is often used in oil and gas. We've looked at a variety of different types of split offs or spin-offs, and those are all effectively just variances on public market spins, investors taking concentrated bets on one or the other as you fractionate the company or privately spinning something.
We've done JVs in the past, as many of you know, with companies like Maze Therapeutics, and we've also effectuated partnerships or asset sales. And I think amidst all of these different considerations, what we've come to the realization of, is in today's marketplace, the highest and best way for us to maximize total return to shareholder, while still being able to push forward important science, is really the carve-out structure, meaning taking assets and spinning them private alongside a great set of syndicate investors, so that ultimately we maintain a substantial stake in that spun organization, and our investors ultimately can gain value from that stake, but that we're not financing it at BridgeBio off of our own balance sheet.
And so the first example of this is, BridgeBio Oncology Therapeutics. As many of you know, we have three very exciting oncology assets that we've been working on almost from the, origination of BridgeBio. The first is what we believe, potentially a best-in-class, G12C on KRAS inhibitor.
The second is, I believe, a first-in-class PI3K alpha breaker mechanism, and the third is a pan-KRAS inhibitor. Two of those compounds are set to go into the clinic in less than 12 months. The third just achieved development candidate, so should be in the clinic in 12-15 months. And so that obviously is gonna require a substantial amount of balance sheet, but it's also a very exciting time for those programs. And so what we were able to do, as some of you may have read, is to achieve a carve-out, whereby we were able to partner with a wonderful group of investors to push forth that program, again, off of the BridgeBio balance sheet, but maintaining BridgeBio ownership in that company.
I should say that, like everything, we try to do as much research as possible to try to understand all of those different strategies, what was gonna maximize total return to shareholder. You can see here that in general, as long as these programs don't fail, something like a carve out ultimately should be able to deliver reasonable, total return to shareholder, for all of you that have been supporting the company, for a long time. So with that, you know, what's next in 2024? Obviously, the infigratinib data, sometime in early June, as I mentioned. Hot on the heels of that will be our phase II data in congenital adrenal hyperplasia, late August, early September, as we mentioned at the outset of the year.
And then stay tuned for regulatory and trial enrollment updates on LGMD2I, a very exciting program that we believe could stand to have some more attention. Phase 3 enrollments on ADH1 updates, and then obviously approval for acoramidis in ATTR cardiomyopathy happening before the end of the year. So with that, maybe I'll wrap up, and I guess I went a little over, but it's just seven minutes for questions. I'll take whatever people have on their minds.
All right. Thank you so much, Neil. We will take questions from the audience. Don't be shy. Just raise your hand, we'll get to you. Maybe to start things off on my end, you mentioned in the past, 45% or so of current patients on Voxzogo would likely switch to infigratinib. What are the assumptions factored into this, and how much is that depends on that having, you know, maybe in line efficacy, but much better administration versus best-in-class efficacy?
Yeah, so we'll have to update that market research. We've seen. You know, the first bit of market research that we did, that I think we had shared publicly, was if we had the same efficacy, but that we- if we were oral and safe, what would the overall share in the marketplace be? And it looked like a majority share based on the profile of the two agents, and this was now some two years ago.
I mean, I think what patients are looking for because, I'm sorry, what the community is looking for, because the impact of these medicines compound over a period of time, is differentiated efficacy, obviously, first and foremost, and the ability to stay safe and stay compliant over a long period of time since you're using the drug, you know, from diagnosis all the way until the growth plate closes. What that specific number is, I don't know, but I think it would be, you know, it would still be consistent with what we saw before, which is majority share if we were in line with efficacy, and then it grows from there.
I also will say that I do think, just given the relatively smaller call point, that many of the KOLs and high prescribers in this space are fairly familiar with the path and mechanism at a fairly deep level of this condition. And so the idea that you are tuning down both of the effector pathways versus one, as long as it's situated in concert with point estimates that are, you know, much better than what we've seen before, it all kinda fits people's view that this should be a more efficacious and also safer and more convenient drug, if our data hangs in there.
Perfect. Any questions? Well, let me follow up with this one. ATTR, silencers versus stabilizers, how does the market, evolve? And, you know, you showed a very interesting slide a couple of weeks ago at a sell-side event, just looking at what the street, is estimating for each of the different, agents in the field. Not a lot of love for acoramidis. What's going on there? What, what is the street missing?
I can't... Yeah, I can't comment on what's going on there, but I may reiterate the baseline of expectation, as we understand it, the market today is about a consensus 8% market share for acoramidis, and you know, and about 60% for the knockdown agent known as vutrisiran. And so a majority coming in on the knockdowns, a minority coming in on orals, and about double of what we had, or slightly over double of what we had, for tafamidis. I'd say as follows, first, our market research suggests that small molecule stabilizers should be first line, and that's very consistent with what you see across cardiovascular categories.
I say that when we feed in the following TPP for the knockdowns that are to come, which is effectively about the same efficacy as what we were able to deliver, but obviously with a different mechanism. And the reason I say that really goes back to the biochemistry here. Effectively, all of these agents are trying to limit the amount of toxic monomer that's depositing in the heart, and we can go into the reasons for this. You can biochemically model it, or you can look at polyneuropathy data. But effectively, the same quantitative amount of knockdown is tantamount to the same amount of stabilization. So a 95% stabilizer should just outperform an 84% mean max knockdown, which should both substantially outperform a 50% stabilizer into tafamidis.
My view, at least, is that from an efficacy standpoint, acoramidis should hold, be able to hold its own, and acoramidis and tafamidis will be battling in that first line for share. For those patients that are not responding, and the good news here is you have things like NT-proBNP that can be used to determine who is not responding and who is responding, they would then move on, I would think, to an orthogonal mechanism like a knockdown. If you play all that out, you know, our best guess is that we're at 25%-30% market share, something similar or slightly lower than what tafamidis achieves, because usually it's hard to displace a first mover, and then the remainder would go to the knockdown agents.
Yeah, and you know, the piece around safety, I think, is also an important piece here, where small molecules obviously are able to spare the tetramer. The tetramer is around for everyone. It's, there's no one who doesn't have it or has a half dose of it. You don't have to take vitamin A supplementation. RBP4 is still moving to the eye. So if you could do everything that you want to do with a small molecule for reasons of convenience, cost, and safety, I think you'd start there, and then for the nonresponders, move to the knockdown. So that is what informs our idea of the market, and then the market research suggests something similar.
Great. Any questions? Please.
Can you, can you speak to how enrollment is going for retinal in phase 3? And then separately, are you guys still collecting data in PROPEL right now that you're gonna top line or share in early June? And if so, are you, are you guys going to be blind into the data at this point?
Yes, for the second. Yes. So, we're gonna share the data just as soon as we get it, in early June, and the final patient comes in for that 18-month time point, and we'll lock the database, in early June. So yeah, we're blinded to it. On the first piece, enrollment's going very well. PROPEL 3, as you might imagine, you could talk to many of the KOLs and sites. It's going ahead of schedule, and that's why we anticipate full enrollment easily this year, with a readout, sometime next year. Yeah.
Do the readouts of PROPEL 2 influence your decision on hypochondroplasia?
That's a great question. They wouldn't, unless PROPEL 2 somehow shows that we no longer have an efficacious agent. But in the context of you know, a continued efficacious agent, not only would it not affect PROPEL 3, but it would also not affect our excitement in and around the hypochondroplasia opportunity, which you know, we should be launching into fairly soon here.
Great. Maybe real quickly, commercial readiness for acoramidis. How do you displace, you know, a first-to-market agent?
Yeah, that's a great question. We, we've been getting a lot of why aren't physicians quite as familiar with some of the data that we've been publishing on recently? I just remind everyone that we're in a very sensitive pre-promotion zone right now, so there's not a lot we can be doing or saying outside of medical conferences in and around our data. But our anticipation is as soon as we gain approval, there's a lot that we can do, and that's why we're publishing so much, so quickly. So in terms of commercial readiness, it really starts with the data. We believe linking greater levels of stabilization, greater and higher levels of serum TTR to better outcomes downstream is really gonna be the cornerstone.
How that's reflected is absolute survival and lower levels of hospitalization, which I think we've seen, and, you know, for those of you that are following this field, I'd pay close attention to continued studies from physicians that have access to both acoramidis and tafamidis at their own sites, analogous to what Dr. Maurer showed in his HFSA talk. I think you're gonna see many more sites just looking at acoramidis and looking at tafamidis and seeing what do those levels of survival, what do those levels of hospitalization look like over time, and then obviously, with publications like we just had at ESC.
So you've got a couple that we've obviously hired an MSL team now that's ready to go as soon as we gain an approval and can be in medical conferences, and a sales team that we've also now hired the senior leaders for, and we'll be obviously out ready to detail when it starts. We won't divulge the exact field force sizing, but it's not gonna be highly controversial. And then we started to put together our LDN, you know, how... What is our SP and SD strategy? How do we think about patient access? All of those things. Are there ways that we can serve the patient community we think even, you know, even better going forward?
We won't, we're not gonna disclose any of that until we launch. Yep.
Perfect. Exciting times. Neil, thank you so much for joining us.
Yeah, thanks for the opportunity.